Pharmacological and Combined Interventions for the Acute Depressive Episode: Focus on Efficacy and Tolerability

Background: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients. Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles. Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted

Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability

Andre R Brunoni1, Renerio Fraguas Jr1, Felipe Fregni21Department and Institute of Psychiatry, University of Sao Paulo, Brazil; 2Laboratory of Neuromodulation, Spaulding Rehabilitation Center, Harvard Medical School and Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USABackground: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients.Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles.Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted.Keywords: acute depressive episode, pharmacological interventions, combined intervention

Neuromodulation as a cognitive enhancement strategy in healthy older adults: promises and pitfalls

Increases in life expectancy have been followed by an upsurge of age-associated cognitive decline. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have risen as promising approaches to prevent or delay such cognitive decline. However, consensus has not yet been reached about their efficacy in improving cognitive functioning in healthy older adults. Here we review the effects of TMS and tDCS on cognitive abilities in healthy older adults. Despite considerable variability in the targeted cognitive domains, design features and outcomes, the results generally show an enhancement or uniform benefit across studies. Most studies employed tDCS, suggesting that this technique is particularly well-suited for cognitive enhancement. Further work is required to determine the viability of these techniques as tools for long-term cognitive improvement. Importantly, the combination of TMS/tDCS with other cognitive enhancement strategies may be a promising strategy to alleviate the cognitive decline associated with the healthy aging process

Changes in Clinical Trials Methodology Over Time: A Systematic Review of Six Decades of Research in Psychopharmacology

Background: There have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years. Methodology/Principal Findings: We performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time. Conclusions/Significance: Clinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials

Study adherence in a tDCS longitudinal clinical trial with people with spinal cord injury

Study design Secondary analysis of a clinical trial.Objectives To analyze adherence to 1-year transcranial Direct Current Stimulation (tDCS) clinical trial in people with chronic pain due to spinal cord injury (SCI). We also explore the association between dropout and several baseline variables such as age, depression levels, pain severity, number of days with pain in the last 7 days, walking ability, sleep, work, relationship with others, and enjoyment with life.Setting Boston, USA.Methods Forty-six participants were enrolled in this trial, and 33 participants were randomized to receive either active or sham tDCS.Results Using the full intention-to-treat (ITT) criteria, only 8 participants (24%) finished the study. The median time to dropout was seven (IQR:6,19) sessions (i.e., immediately after the first follow-up), regardless of the type of stimulation that participants received (active vs. sham tDCS) (chi(2) = 0.025, p = 0.875). An exploratory analysis suggested that only the number of days with pain in the last 7 days was moderately associated with dropout, with people experiencing less pain being more prone to dropout from the study.Conclusions Despite all the measures to improve study adherence (such as providing parking, flexibility to schedule sessions, follow-up with participants by phone), it seems that long follow-up periods may increase the likelihood of dropout. Given the need to understand long-term effects of interventions, longitudinal trials need to consider alternative designs or methods of treatment (for instance home treatment or home assessment) to decrease attrition rate.This project was supported by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR grant numbers H133N110010 and 90SI5021-01-00). SC and JL are supported by the Portuguese Foundation for Science and Technology PTDC/MHC-PCN/3950/2014; SC is also funded by the following FCT grant IF/00091/2015

Feasibility of remotely-supervised tDCS in a person with neuropathic pain due to spinal cord injury

[Excerpt] Nearly 40% of people with spinal cord injury (SCI) report neuropathic pain that is often refractory to medications.1,2 Substantial research has shown that anodal transcranial direct current stimulation (tDCS) over the motor cortex can induce clinically significant pain relief in chronic pain.3–6 However, these clinical trials often require multiple study visits per trial and are associated to poor adherence to the study protocol. For instance, in our recent tDCS study in SCI, only 7 participants from the initial 46 that were enrolled completed the study.7 In fact, despite all attempts to improve adherence, such as flexibility to schedule sessions, free parking and follow-ups by the phone, most participants ended up dropping out from the study. Since many people with SCI have limited mobility, alternatives for home-based care are needed. Here we report the feasibility of supervised home-based tDCS application in a 57-year old woman with tetraplegia and sublesional neuropathic pain secondary to SCI since 2012. At time of enrollment, she self-reported pain as being 9 out of 10 in a visual analogue scale. [...]This project was supported by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR grant numbers 90DP0035 and H133N110010)

Recuperação pós-eletroconvulsoterapia: comparação entre propofol, etomidato e tiopental

OBJECTIVES: To compare post anesthetic time for patient recovery after electroconvulsive therapy, as measured by the post anesthetic Recovery Score of Aldrete and Kroulik, using three different types of hypnotic drugs (propofol, etomidate and thiopental). METHOD: Thirty patients were randomized to receive one of the three drugs (n = 10 in each group), during a course of electroconvulsive therapy treatment. Patients and raters were blinded to which drug was received. Main treatment characteristics were recorded (as total electric charge received seizure threshold, number of treatments, and the mean time for recovery) along the whole treatment. RESULTS: Thiopental and propofol were associated with a significance increase in charge needed to induce a seizure (p < 0.0001) when compared to etomidate, as well as a significant decrease of time for recovery (p = 0.042). CONCLUSIONS: These findings suggest that, although there seems to be no difference in the clinical outcome across these three drugs, propofol offers the best recovery profile. However, it makes a higher mean electric charge necessary.OBJETIVOS: Comparar o tempo de recuperação dos pacientes após eletroconvulsoterapia avaliada com a escala de recuperação pós-anestésica de Aldrete e Kroulik, utilizando três tipos de medicações anestésicas (propofol, etomidato and tiopental). MÉTODO: Trinta pacientes foram randomizados para receber uma das medicações (n = 10 em cada grupo) durante uma série de tratamentos com eletroconvulsoterapia. Os pacientes e o examinador ficaram cegos para o tipo de anestésico utilizado. As principais características do tratamento foram avaliadas (como carga total de eletricidade recebida, limiar convulsivo, número de sessões e o tempo médio para recuperação) ao longo de toda a série de tratamentos. RESULTADOS: Tiopental e propofol se associaram a um aumento significativo na carga elétrica total utilizada (p < 0,0001) quando comparados com etomidato, bem como uma diminuição significativa no tempo de recuperação pós-anestésica (p = 0,042). CONCLUSÕES: Estes achados sugerem que, apesar de não haver diferença na evolução clínica entre os três grupos estudados, a droga propofol oferece o melhor perfil de recuperação apesar de requerer uma carga elétrica média maior

Transcranial direct current stimulation as an add-on treatment to cognitive-behavior therapy in first episode drug-naive major depression patients: the ESAP study protocol

Background: Major Depressive Disorder (MDD) affects more than 264 million people worldwide. Current treatments include the use of psychotherapy and/or drugs, however similar to 30% of patients either do not respond to these treatments, or do not tolerate the side effects associated to the use of pharmacological interventions. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters. Several studies demonstrated that transcranial Direct Current Stimulation (tDCS) can be effective for symptoms relief in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other interventions.Methods/Design: This is a study protocol for a parallel, randomized, triple-blind, sham-controlled clinical trial in which a total of 90 drug-naive, first-episode MDD patients (45 per arm) will be randomized to one of two groups to receive a 6-weeks of CBT combined with either active or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). The primary outcome will depressive symptoms improvement as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) at 6-weeks. The secondary aim is to test whether CBT combined with tDCS can engage the proposed mechanistic target of restoring the prefrontal imbalance and connectivity through the bilateral modulation of the DLPFC, as assessed by changes over resting-state and emotional task eliciting EEG.Discussion: This study evaluates the synergetic clinical effects of CBT and tDCS in the first episode, drug-naive, patients with MDD. First episode MDD patients provide an interesting opportunity, as their brains were not changed by the pharmacological treatments, by the time course, or by the recurrence of MDD episodes (and other comorbidities).This work was partially supported by FEDER funds through the Programa Operacional Factores de Competitividade-COMPETE and by national funds through FCT-Fundacao para a Ciencia e a Tecnologia through the calls IF/00091/2015 and PTDC/PSI-ESP/29701/2017. The sponsors had no role in the study design, implementation, data analysis or publication