Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis

Background: Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device-rTMS) trials. Methodology/Principal Findings: We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria-29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d-random-effects model-1.48; 95% C.I. 1.26 to 1.6) and rTMS studies (0.82; 95% C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized. Conclusions/Significance: We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself.

Non-pharmacological approach to neuropathic pain: the use of repetitive transcranial magnetic stimulation

Neuromodulation is the branch of neurophysiology related to the therapeutic effects of electrical stimulations of the nervous system. There are currently different practical applications of neuromodulation techniques for the treatment of various neurological disorders, such as deep brain stimulation for Parkinson`s disease and repetitive transcranial magnetic stimulation (rTMS) for major depression. An increasing number of studies have been devoted to the analgesic effects of rTMS in chronic pain patients. RTMS has been used either as a therapeutic tool per se, or as a preoperative test in patients undergoing epidural precentral gyrus stimulation. High-frequency rTMS (a parts per thousand yen5 Hz) is considered to be excitatory, while low-frequency stimulation (a parts per thousand currency sign1 Hz) is considered to exert an inhibitory effect over neuronal populations of the primary motor cortex. However, other parameters of stimulation may play a central role on its clinical effects such as the type of coil, its orientation over the scalp, and the total number of rTMS sessions performed. Experimental data from animals, healthy volunteers, and neuropathic pain patients have suggested that stimulation of the primary motor cortex by rTMS is able to activate brain regions implicated in the processing of the different aspects of chronic pain, and influence brain regions involved in the endogenous opioid system. Over twenty prospective randomized sham-controlled trials have studied the analgesic effects of rTMS on chronic pain. Most of the patients included in these trials had central or peripheral neuropathic pain. Although most studies used a single session of stimulation, recent studies have shown that the analgesic effects of rTMS may outlast the stimulation period for many days when repetitive sessions are performed. This opens the possibility to use rTMS as a therapeutic tool of its own in the armamentarium against neuropathic pain.

Responsiveness of sensorimotor cortex during pharmacological intervention with bromazepam

The aim of this study was to investigate the influence of bromazepam on EEG and the motor learning process when healthy subjects were submitted to a typewriting task. We investigated bromazepam due to its abuse by various populations and its prevalent clinical use among older individuals which are more sensitive to the negative effects of long half-life benzodiazepines. A randomized double-blind design was used with subjects divided into three groups: placebo (n = 13), bromazepam 3 mg (n = 13) and bromazepam 6 mg (n = 13). EEG data comprising theta, alpha and beta bands was recorded before, during and after the motor task. Our results showed a lower relative power value in the theta band in the Br 6 mg group when compared with PL. We also observed a reduction in relative power in the beta band in the Br 3 mg and Br 6 mg when compared with PL group. These findings suggest that Br can contribute to a reduced working memory load in areas related to attention processes. On the other hand, it produces a higher cortical activation in areas associated with sensory integration. Such areas are responsible for accomplishing the motor learning task. The results are an example of the usefulness of integrating electrophysiological data, sensorimotor activity and a pharmacological approach to aid in our understanding of cerebral changes produced by external agents. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Exercise improves cardiovascular control in a model of dislipidemia and menopause

The present study investigated the effects of exercise training on arterial pressure, baroreflex sensitivity, cardiovascular autonomic control and metabolic parameters on female LDL-receptor knockout ovariectomized mice. Mice were divided into two groups: sedentary and trained. Trained group was submitted to an exercise training protocol. Blood cholesterol was measured. Arterial pressure (AP) signals were directly recorded in conscious mice. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses to AP changes. Cardiovascular autonomic modulation was measured in frequency (FFT) and time domains. Maximal exercise capacity was increased in trained as compared to sedentary group. Blood cholesterol was diminished in trained mice (191 +/- 8 mg/dL) when compared to sedentary mice (250 +/- 9 mg/dL, p<0.05). Mean AP and HR were reduced in trained group (101 +/- 3 mmHg and 535 +/- 14 bpm, p<0.05) when compared with sedentary group (125 +/- 3 mmHg and 600 +/- 12 bpm). Exercise training induced improvement in bradycardic reflex response in trained animals (-4.24 +/- 0.62 bpm/mmHg) in relation to sedentary animals (-1.49 +/- 0.15 bpm/mmHg, p<0.01); tachycardic reflex responses were similar between studied groups. Exercise training increased the variance (34 +/- 8 vs. 6.6 +/- 1.5 ms(2) in sedentary, p<0.005) and the high-frequency band (HF) of the pulse interval (IP) (53 +/- 7% vs. 26 +/- 6% in sedentary, p<0.01). It is tempting to speculate that results of this experimental study might represent a rationale for this non-pharmacological intervention in the management of cardiovascular risk factors in dyslipidemic post-menopause women. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Cardiovascular prevention in HIV patients: Results from a successful intervention program

Objectives: To analyze the effect of a prevention program oil the estimated cardiovascular risk calculated by three risk scores. Methods: We prospectively evaluated 87 HIV+ patients with elevated cardiovascular risk estimation. Framirigham (FIRS), PROCAM and National Cholesterol Education Program (ATP-III) were applied. Cardiovascular risk was defined as elevated if >10%. All patients received non-pharmacological (diet, exercise, smoking cessation) and, when appropriate, pharmacological therapy. Results: Mean age was 52 years, 92% were male, 39.1% were smokers, 70.1% had hypertension, 18.4% had diabetes. All patients were under HAART, 56.3% were receiving protease inhibitors (131). After 6 months, intervention was associated to significant changes oil triglycerides (298 242 and 206 +/- 135 mg/dL, p<0.05), total-cholesterol (224 +/- 47 and 189 +/- 38 mg/dL, p<0.001). LDL-cholesterol (129 +/- 44 and 109 +/- 30 mg/dL,p<0.001). Frequencies of patients with elevated cardiac risk before and 6 months after intervention were 92% x 27.6% (p < 0.0001), 80.5% x 50.6% (p < 0.0002), and 25.3% x 14.9% (p = 0.12), for FIRS, ATP III and PROCAM, respectively. Conclusions: An intervention Program focused on reduction of traditional risk factors was able to decrease the frequency of patients with HIV infection and elevated cardiovascular risk estimation. FIRS showed greater sensitivity than the other scores. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

The effects of skin-to-skin contact during acute pain in preterm newborns

Background and purpose: Several promising non-pharmacological interventions have been developed to reduce acute pain in preterm infants including skin-to-skin contact between a mother and her infant. However, variability in physiological outcomes of existing studies on skin-to-skin makes it difficult to determine treatment effects of this naturalistic approach for the preterm infant. The aim of this study was to test the efficacy of mother and infant skin-to-skin contact during heel prick in premature infants. Method: Fifty nine stable preterm infants (born at least 30 weeks gestational age) who were undergoing routine heel lance were randomly assigned to either 15 min of skin-to-skin contact before, during and following heel prick (n = 31, treatment group), or to regular care (n = 28, control group). Throughout the heel lance procedure, all infants were assessed for change in facial action (NFCS), behavioral state, crying, and heart rate. Results: Statistically significant differences were noted between the treatment and control groups during the puncture, heel squeeze and the post phases of heel prick. Infants who received skin-to-skin contact were more likely to show lower NFCS scores throughout the procedure. Both groups of infants cried and showed increased heart rate during puncture and heel squeeze although changes in these measures were less for the treated infants. Conclusions: Skin-to-skin contact promoted reduction in behavioral measures and less physiological increase during procedure. It is recommended that skin-to-skin contact be used as a non-pharmacologic intervention to relieve acute pain in stable premature infants born 30 weeks gestational age or older. (C) 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

Effect of a sequential education and monitoring programme on quality-of-life components in heart failure

Aims Trials of disease management programmes (DMP) in heart failure (HF) have shown controversial results regarding quality of life. We hypothesized that a DMP applied over the long-term could produce different effects on each of the quality-of-life components. Methods and results We extended the prospective, randomized REMADHE Trial, which studied a DMP in HF patients. We analysed changes in Minnesota Living with Heart Failure Questionnaire components in 412 patients, 60.5% male, age 50.2 +/- 11.4 years, left ventricular ejection fraction 34.7 +/- 10.5%. During a mean follow-up of 3.6 +/- 2.2 years, 6.3% of patients underwent heart transplantation and 31.8% died. Global quality-of-life scores improved in the DMP intervention group, compared with controls, respectively: 57.5 +/- 3.1 vs. 52.6 +/- 4.3 at baseline, 32.7 +/- 3.9 vs. 40.2 +/- 6.3 at 6 months, 31.9 +/- 4.3 vs. 41.5 +/- 7.4 at 12 months, 26.8 +/- 3.1 vs. 47.0 +/- 5.3 at the final assessment; P<0.01. Similarly, the physical component (23.7 +/- 1.4 vs. 21.1 +/- 2.2 at baseline, 16.2 +/- 2.9 vs. 18.0 +/- 3.3 at 6 months, 17.3 +/- 2.9 vs. 23.1 +/- 5.7 at 12 months, 11.4 +/- 1.6 vs. 19.9 +/- 2.4 final; P<0.01), the emotional component (13.2 +/- 1.0 vs. 12.1 +/- 1.4 at baseline, 11.7 +/- 2.7 vs. 12.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 16.8 +/- 5.9 at 12 months, 6.7 +/- 1.0 vs. 10.6 +/- 1.4 final; P<0.01) and the additional questions (20.8 +/- 1.2 vs. 19.3 +/- 1.8 at baseline, 14.3 +/- 2.7 vs. 17.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 21.0 +/- 5.5 at 12 months, 6.7 +/- 1.4 vs. 17.3 +/- 2.2 final; P<0.01) were better (lower) in the intervention group. The emotional component improved earlier than the others. Post-randomization quality of life was not associated with events. Conclusion Components of the quality-of-life assessment responded differently to DMP. These results indicate the need for individualized DMP strategies in patients with HF. Trial registration information www.clincaltrials.gov NCT00505050-REMADHE.

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting

The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD. RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections: [1] epidemiology and pathophysiology of MDD; [2] a comprehensive overview of the neuromodulation techniques; [3] using neuromodulation techniques in MDD associated with non-psychiatric conditions; [4] the main challenges of neuromodulation research and alternatives to overcome them. DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.

Redução da pressão arterial e do duplo produto de repouso após treinamento resistido em idosas hipertensas

FUNDAMENTO: Em razão das controvérsias existentes na literatura quanto aos possíveis benefícios do treinamento resistido (TR) sobre a pressão arterial de repouso (PA) e por causa da escassez de estudos com indivíduos idosos e hipertensos, o TR é pouco recomendado como forma de tratamento não-farmacológico da hipertensão arterial. OBJETIVO: Verificar os efeitos do TR progressivo sobre a pressão arterial de repouso (PA), a freqüência cardíaca (FC) e o duplo produto (DP) em idosas hipertensas controladas. MÉTODOS: Vinte mulheres idosas (66,8 ± 5,6 anos de idade) sedentárias, controladas com medicação anti-hipertensiva, realizaram 12 semanas de TR, compondo o grupo do treinamento resistido (GTR). Vinte e seis idosas (65,3 ± 3,4 anos de idade) hipertensas controladas não realizaram exercícios físicos durante a pesquisa, constituindo o grupo-controle. RESULTADOS: Houve redução significativa nos valores de repouso da pressão arterial sistólica (PAS), da pressão arterial média (PAM) e do DP após o TR. Não foram encontradas reduções significativas na pressão arterial diastólica (PAD) e na FC de repouso após o TR em ambos os grupos. A magnitude da queda no GTR foi de 10,5 mmHg, 6,2 mmHg e 2.218,6 mmHg x bpm para a PAS, PAM e o DP, respectivamente. CONCLUSÃO: O TR progressivo reduziu a PAS, PAM e o DP de repouso de idosas hipertensas, controladas com medicação anti-hipertensiva.

Challenges and opportunities for primary, secondary, and tertiary prevention of Chagas' disease

A century after its discovery, Chagas' disease still represents a major public health challenge in Latin America. Moreover, because of growing population movements, an increasing number of cases of imported Chagas' disease have now been detected in non-endemic areas, such as North America and some European countries. This parasitic zoonosis, caused by Trypanosoma cruzi, is transmitted to humans by infected Triatominae insects, or occasionally by non-vectorial mechanisms, such as blood transfusion, mother to fetus, or oral ingestion of materials contaminated with parasites. Following the acute phase of the infection, untreated individuals enter a chronic phase that is initially asymptomatic or clinically unapparent. Usually, a few decades later, 40-50% of patients develop progressive cardiomyopathy and/or motility disturbances of the oesophagus and colon. In the last decades several interventions targeting primary, secondary and tertiary prevention of Chagas' disease have been attempted. While control of both vectorial and blood transfusion transmission of T cruzi (primary prevention) has been successful in many regions of Latin America, early detection and aetiological treatment of asymptomatic subjects with Chagas' disease (secondary prevention) have been largely underutilised. At the same time, in patients with established chronic disease, several pharmacological and non-pharmacological interventions are currently available and have been increasingly used with the intention of preventing or delaying complications of the disease (tertiary prevention). In this review we discuss in detail each of these issues.

SCFAs Induce Mouse Neutrophil Chemotaxis through the GPR43 Receptor

Short chain fatty acids (SCFAs) have recently attracted attention as potential mediators of the effects of gut microbiota on intestinal inflammation. Some of these effects have been suggested to occur through the direct actions of SCFAs on the GPR43 receptor in neutrophils, though the precise role of this receptor in neutrophil activation is still unclear. We show that mouse bone marrow derived neutrophils (BMNs) can chemotax effectively through polycarbonate filters towards a source of acetate, propionate or butyrate. Moreover, we show that BMNs move with good speed and directionality towards a source of propionate in an EZ-Taxiscan chamber coated with fibrinogen. These effects of SCFAs were mimicked by low concentrations of the synthetic GPR43 agonist phenylacetamide-1 and were abolished in GPR43(-/-) BMNs. SCFAs and phenylacetamide-1 also elicited GPR43-dependent activation of PKB, p38 and ERK and these responses were sensitive to pertussis toxin, indicating a role for Gi proteins. Phenylacetamide-1 also elicited rapid and transient activation of Rac1/2 GTPases and phosphorylation of ribosomal protein S6. Genetic and pharmacological intervention identified important roles for PI3K gamma, Rac2, p38 and ERK, but not mTOR, in GPR43-dependent chemotaxis. These results identify GPR43 as a bona fide chemotactic receptor for neutrophils in vitro and start to define important elements in its signal transduction pathways.

Post-resistance exercise hypotension in spontaneously hypertensive rats is mediated by nitric oxide

1. Postexercise hypotension (PEH) plays an important role in the non-pharmacological treatment of hypertension. It is characterized by a decrease in blood pressure (BP) after a single bout of exercise in relation to pre-exercise levels. 2. The present study investigated the effect of a single session of resistance exercise, as well as the effect of nitric oxide (NO) and the autonomic nervous system (ANS), in PEH in spontaneously hypertensive rats (SHR). 3. Catheters were inserted into the left carotid artery and left jugular vein of male SHR (n = 37) for the purpose of measuring BP or heart rate (HR) and drug or vehicle administration, respectively. Haemodynamic measurements were made before and after acute resistance exercise. The roles of NO and the ANS were investigated by using N(G)-nitro-L-arginine methyl ester (L-NAME; 15 mg/kg, i.v.) and hexamethonium (20 mg/kg, i.v.) after a session of acute resistance exercise. 4. Acute resistance exercise promoted a pronounced reduction in systolic and diastolic BP (-37 +/- 1 and -8 +/- 1 mmHg, respectively; P < 0.05), which was suppressed after treatment with L-NAME. The reduction in systolic BP caused by exercise (-37 +/- 1 mmHg) was not altered by the administration of hexamethonium (-38 +/- 2 mmHg; P > 0.05). After exercise, the decrease in diastolic BP was greater with hexamethonium (-26 +/- 1 mmHg; P < 0.05) compared with the decrease caused by exercise alone. 5. The results suggest that acute resistance exercise has an important hypotensive effect on SHR and that NO plays a crucial role in this response.

Adaptations in autonomic function during exercise training in heart failure

Although neurohumoral excitation is the hallmark of heart failure (HF), the mechanisms underlying this alteration are not entirely known. Abnormalities in several systems contribute to neurohumoral excitation in HF, including arterial and cardiopulmonary baroreceptors, central and peripheral chemoreceptors, cardiac chemoreceptors, and central nervous system abnormalities. Exercise intolerance is characteristic of chronic HF, and growing evidence strongly suggests that exercise limitation in patients with chronic HF is not due to elevated filling pressures or inadequate cardiac output during exercise, but instead due to skeletal myopathy. Several lines of evidence suggest that sympathetic excitation contributes to the skeletal myopathy of HF, since sympathetic activity mediates vasoconstriction at rest and during exercise likely restrains muscle blood flow, arteriolar dilatation, and capillary recruitment, leading to underperfused areas of working muscle, and areas of muscle ischemia, release of reactive oxygen species (ROS), and inflammation. Although controversial, either unmyelinated, metabolite-sensitive afferent fibers, and/or myelinated, mechanosensitive afferent fibers in skeletal muscle underlie the exaggerated sympathetic activity in HF. Exercise training has emerged as a unique non-pharmacological strategy for the treatment of HF. Regular exercise improves functional capacity and quality of life, and perhaps prognosis in chronic HF patients. Recent studies have provided convincing evidence that these benefits in chronic HF patients are mediated by significant reduction in central sympathetic outflow as a consequence of improvement in arterial and chemoreflex controls, and correction of central nervous system abnormalities, and increase in peripheral blood flow with reduction in cytokines and increase in mass muscle.

Selective Vagal Denervation of the Sinus and Atrioventricular Nodes, Guided by Vagal Reflexes Induced by High Frequency Stimulation, to Treat Refractory Neurally Mediated Syncope

Vagal Denervation and Neurally Mediated Syncope. A 15-year-old female patient presented with frequent episodes of vasovagal syncope refractory to non-pharmacological and pharmacological measures. Two tilt-table tests performed before and after conventional therapy were positive and reproduced the patient`s clinical symptoms. Selective vagal denervation, guided by HFS, was performed. Six radiofrequency pulses were applied on the left and right sides of the interatrial septum, abolishing vagal responses at these locations. Basal sinus node and Wenckebach cycle lengths changed significantly following ablation. A tilt test performed after denervation was negative and revealed autonomic tone modification. The patient reported significant improvement in quality of life and remained asymptomatic for 9 months after denervation. After this period, three episodes of NMS occurred during a 4-month interval and a tilt test performed 11 months after the procedure demonstrated vagal activity recovery. (J Cardiovasc Electrophysiol, Vol. 20, pp. 558-563, May 2009).

Cannabidiol for the treatment of psychosis in Parkinson`s disease

The management of psychosis in Parkinson`s disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson`s Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.