Verònica Gálvez

Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial {

BACKGROUND Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: An open-label pilot study

BACKGROUND Several recent trials have reported transcranial direct current stimulation (tDCS) to be effective in treating depression, though the relative benefits of different electrode montages remain unexplored. Whereas all recent studies have used a bifrontal (BF) electrode montage, studies published in the 1960s and 1970s placed one electrode in an extracephalic position, with some positive reports of efficacy. This study investigated the efficacy and safety of tDCS given with a fronto-extracephalic (F-EX) montage. METHODS 2 mA tDCS was administered for 20 min every weekday over four weeks in 11 participants with a Major Depressive Episode who had previously shown inadequate response to, or relapsed following, a course of BF tDCS. For F-EX tDCS the anode was placed on the left dorsolateral prefrontal cortex and the cathode on the right upper arm. Depression severity and neuropsychological function were assessed before and after the treatment course. Antidepressant response was compared across an equivalent treatment period for both montages. RESULTS F-EX tDCS was shown to be safe and well tolerated. Depression ratings improved after acute treatment on the Montgomery Åsberg Depression Rating Scale (p < 0.001). Participants showed greater initial treatment response with F-EX tDCS than with BF tDCS (p < 0.001). LIMITATIONS This was an open label pilot study. The two comparison treatments were applied consecutively. CONCLUSION F-EX tDCS appears to be safe and to have antidepressant effects, and may lead to more rapid improvement than tDCS given with a BF montage.

Hypomania induction in a patient with bipolar II disorder by transcranial direct current stimulation (tDCS).

Objectives: To report a case of hypomania induced by transcranial direct current stimulation (tDCS) given with an extracephalic reference electrode. Transcranial direct current stimulation is a noninvasive brain stimulation technique in which a weak current is applied through the scalp to produce changes in neuronal excitability in the underlying cerebral tissue. Recent clinical trials have shown promising results with left anodal prefrontal tDCS in treating depression. When the reference cathodal electrode in tDCS is moved from the cranium to an extracephalic position, larger areas of both cerebral hemispheres are stimulated, with potential implications for both efficacy and safety. Methods: We report the case of a 33-year-old female with bipolar II disorder, on mood stabilizer medication, who had previously participated in a clinical trial of tDCS given with a bifrontal electrode montage for the treatment of major depression without incident, but became hypomanic when she received a later course of tDCS given with a frontoextracephalic configuration. Factors contributing to the development of hypomania in the second course of tDCS are examined. Results: No substantial differences were found in the patients clinical presentation between the 2 tDCS courses to explain the emergence of hypomania only after the second course. The different montage used in the second course appeared to be the main contributory factor in the induction of hypomania. Conclusions: The reported case suggests that frontoextracephalic tDCS has antidepressant properties and the potential to induce hypomanic symptoms. In particular, it raises the question of whether frontoextracephalic tDCS requires additional precautions when administered to bipolar patients compared to bifrontal tDCS.

Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis

Background: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. Methods: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Results: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1–0.4mg/kg i.v., and another assessed 0.1–0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. Conclusion: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

This pilot study assessed the feasibility, efficacy and safety of an individual dose‐titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine.

Side-effects associated with ketamine use in depression: a systematic review

This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.

Predictors of Seizure Threshold in Right Unilateral Ultrabrief Electroconvulsive Therapy: Role of Concomitant Medications and Anaesthesia Used

BACKGROUND An individualized approach to maximize electroconvulsive therapy (ECT) efficacy and minimize cognitive side effects is to treat patients relative to their seizure threshold (ST). However, although Right Unilateral-Ultrabrief (0.3 ms) (RUL-UB) ECT is increasingly used in clinical settings as an effective form of ECT with minimal cognitive effects, there is sparse data regarding predictors of ST. OBJECTIVE To analyze the relationship between ST and clinical and demographic factors in a sample of patients treated with RUL-UB ECT. METHODS Clinical, demographic and ECT data from 179 patients in ECT research studies were examined. Seizure threshold was titrated at the first ECT session. ECT was performed with a Thymatron(®) or Mecta(®) device, with thiopentone (2.5-5 mg/kg) or propofol (1-2 mg/kg) anaesthesia. Medications taken at the time of ST titration were documented. The association between ST and candidate predictor variables was examined with regression analysis. RESULTS Multiple regression analyses showed that 34% of the variance in ST (P < 0.001) could be predicted. Older age (R(2) = 0.194, P < 0.001), propofol (vs thiopentone) (R(2) = 0.029, P ≤ 0.01) and higher anaesthetic dose (mg in propofol equivalents) (R(2) = 0.029, P < 0.05) were found to be predictors of higher initial ST. Treatment with lithium (R(2) = 0.043, P < 0.01) and study site (R(2) = 0.019, P < 0.05) significantly predicted lower initial ST. CONCLUSIONS Empirical titration is recommended for accurate determination of ST in patients receiving RUL-UB ECT. Novel findings of this study are that propofol anaesthesia resulted in higher ST than thiopentone and concomitant treatment with lithium treatment lowered ST.

Transcranial direct current stimulation treatment protocols: should stimulus intensity be constant or incremental over multiple sessions?

Interest in transcranial direct current stimulation (tDCS) as a new tool in neuropsychiatry has led to the need to establish optimal treatment protocols. In an intra-individual randomized cross-over design, 11 healthy volunteers received five tDCS sessions to the left primary motor cortex on consecutive weekdays at a constant or gradually increasing current intensity, in two separate weeks of testing. Cortical excitability was assessed before and after tDCS at each session through peripheral electromyographic recordings of motor-evoked potentials. Both conditions led to significant cumulative increases in cortical excitability across the week but there were no significant differences between the two groups. Motor thresholds decreased significantly from Monday to Friday in both conditions. This study demonstrated that, in the motor cortex, administration of tDCS five times per week whether at a constant intensity or at a gradually increasing intensity was equally effective in increasing cortical excitability.

Eficacia y patrón de uso de la terapia electroconvulsiva de continuación y mantenimiento en el trastorno depresivo mayor

Patients with major depressive disorder (MDD) who require an acute course of electroconvulsive therapy (ECT) have high relapse rates. Therefore, an effective maintenance treatment strategy needs to be established. Continuation and maintenance ECT (C/M-ECT) could be an adequate treatment option, although the lack of controlled studies has led to its usefulness being questioned. This review includes a detailed description of studies on the effectiveness/efficacy of ECT in MDD. Despite their methodological limitations, the results appear to support the idea that C/M-ECT would be a safe and effective alternative, especially in patients with severe and recurrent disease. Nevertheless, more controlled studies are needed to provide new evidence and allow a more accurate assessment of the efficacy, safety and pattern of use of C/M-ECT.

Neuromodulation Therapies for Geriatric Depression

Depression is frequent in old age and its prognosis is poorer than in younger populations. The use of pharmacological treatments in geriatric depression is limited by specific pharmacodynamic age-related factors that can diminish tolerability and increase the risk of drug interactions. The possibility of modulating cerebral activity using brain stimulation techniques could result in treating geriatric depression more effectively while reducing systemic side effects and medication interactions. This may subsequently improve treatment adherence and overall prognosis in the older patient. Among clinically available neuromodulatory techniques, electroconvulsive therapy (ECT) remains the gold standard for the treatment of severe depression in the elderly. Studies have proven that ECT is more effective and has a faster onset of action than antidepressants in the treatment of severe, unipolar, geriatric depression and that older age is a predictor of rapid ECT response and remission. The application of novel and more tolerable forms of ECT for geriatric depression is currently being examined. Preliminary results suggest that right unilateral ultrabrief ECT (RUL-UB ECT) is a promising intervention, with similar efficacy to brief-pulse ECT and fewer adverse cognitive effects. Overall findings in repetitive transcranial magnetic stimulation (rTMS) suggest that it is a safe intervention in geriatric depression. Higher rTMS stimulation intensity and more treatments may need to be given in the elderly to achieve optimal results. There is no specific data on vagus nerve stimulation in the elderly. Transcranial direct current stimulation, magnetic seizure therapy and deep brain stimulation are currently experimental, and more data from geriatric samples is needed.