Transcranial Random Noise Stimulation for the Acute Treatment of Depression: A Randomized Controlled Trial.

BACKGROUND: Transcranial electrical stimulation has broad potential as a treatment for depression. Transcranial random noise stimulation, which delivers randomly fluctuating current intensities, may have greater cortical excitatory effects compared with other forms of transcranial electrical stimulation. We therefore aimed to investigate the antidepressant efficacy of transcranial random noise stimulation. METHODS: Depressed participants were randomly assigned by computer number generator to receive 20 sessions of either active or sham transcranial random noise stimulation over 4 weeks in a double-blinded, parallel group randomized-controlled trial. Transcranial random noise stimulation was delivered for 30 minutes with a direct current offset of 2 mA and a random noise range of 2 mA. Primary analyses assessed changes in depression severity using the Montgomery-Asperg Depression Rating Scale. Neuroplasticity, neuropsychological, and safety outcomes were analyzed as secondary measures. RESULTS: Sixty-nine participants were randomized, of which 3 discontinued treatment early, leaving 66 (sham n = 34, active n = 32) for per-protocol analysis. Depression severity scores reduced in both groups (Montgomery-Asperg Depression Rating Scale reduction in sham = 7.0 [95% CI = 5.0-8.9]; and active = 5.2 [95% CI = 3.2-7.3]). However, there were no differences between active and sham groups in the reduction of depressive symptoms or the number of participants meeting response (sham = 14.7%; active = 3.1%) and remission criteria (sham = 5.9%; active = 0%). Erythema, paresthesia, fatigue, and dizziness/light-headedness occurred more frequently in the active transcranial random noise stimulation group. Neuroplasticity, neuropsychological, and acute cognitive effects were comparable between groups. CONCLUSION: Our results do not support the use of transcranial random noise stimulation with the current stimulation parameters as a therapeutic intervention for the treatment of depression. CLINICAL TRIAL REGISTRATION AT CLINICALTRIALS: gov/NCT01792414.

The Clinical Alliance and Research in Electroconvulsive Therapy Network: An Australian Initiative for Improving Service Delivery of Electroconvulsive Therapy.

OBJECTIVE: There is currently substantial heterogeneity in electroconvulsive therapy (ECT) treatment methods between clinical settings. Understanding how this variation in clinical practice is related to treatment outcomes is essential for optimizing service delivery. The Clinical Alliance and Research in ECT Network is a clinical and research framework with the aims of improving clinical practice, enabling auditing and benchmarking, and facilitating the collection of naturalistic clinical data. METHODS: The network framework and clinical and treatment variables collected and rationale for the use of particular outcome measures are described. Survey results detailing the use of ECT across initial participating clinical centers were examined. RESULTS: The data are reported from 18 of 22 participating centers, the majority based in Australia. Melancholic unipolar depression was the most common clinical indication (78%). Right unilateral (44%) and bifrontal (39%) were the most commonly used electrode placements. Eighty one percent of the centers used individual seizure titration for initial dosing. CONCLUSIONS: There was substantial heterogeneity in the use of ECT between participating centers, indicating that the Network is representative of modern ECT practice. The Clinical Alliance and Research in ECT Network may therefore offer the opportunity to improve service delivery and facilitate the investigation of unresolved research questions pertaining to modern ECT practice.

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is increasingly being utilised as a treatment option for depression, and with this comes a need for a practical review of safety issues intended for clinicians. This article provides an overview of the current literature regarding safety issues with rTMS for depression, and provides recommendations for clinical practice. CONCLUSIONS: Overall, rTMS is a well-tolerated treatment with common side effects (such as headache or local pain at the site of stimulation) being mild. Severe adverse effects, such as seizures, hearing impairment or mania, are uncommon. Certain populations, including adolescents, pregnant women, older adults and those with metal/electronic implants, require special consideration when prescribing and monitoring treatment courses. With adequate assessment and monitoring processes, rTMS can be administered safely in a large proportion of depressed patients.

Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression.

OBJECTIVE: To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. METHODS: In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. RESULTS: Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. CONCLUSION: Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505).

Seizure threshold increases can be predicted by EEG quality in right unilateral ultrabrief ECT.

Increases in seizure threshold (ST) over a course of brief pulse ECT can be predicted by decreases in EEG quality, informing ECT dose adjustment to maintain adequate supra-threshold dosing. ST increases also occur over a course of right unilateral ultrabrief (RUL UB) ECT, but no data exist on the relationship between ST increases and EEG indices. This study (n = 35) investigated if increases in ST over RUL UB ECT treatments could be predicted by a decline in seizure quality. ST titration was performed at ECT session one and seven, with treatment dosing maintained stable (at 6-8 times ST) in intervening sessions. Seizure quality indices (slow-wave onset, mid-ictal amplitude, regularity, stereotypy, and post-ictal suppression) were manually rated at the first supra-threshold treatment, and last supra-threshold treatment before re-titration, using a structured rating scale, by a single trained rater blinded to the ECT session being rated. Twenty-one subjects (60%) had a ST increase. The association between ST changes and EEG quality indices was analysed by logistic regression, yielding a significant model (p < 0.001). Initial ST (p < 0.05) and percentage change in mid-ictal amplitude (p < 0.05) were significant predictors of change in ST. Percentage change in post-ictal suppression reached trend level significance (p = 0.065). Increases in ST over a RUL UB ECT course may be predicted by decreases in seizure quality, specifically decline in mid-ictal amplitude and potentially in post-ictal suppression. Such EEG indices may be able to inform when dose adjustments are necessary to maintain adequate supra-threshold dosing in RUL UB ECT.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial.

BACKGROUND: Animal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. METHODS: This pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h-48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h-48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. RESULTS: The subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. LIMITATIONS: Pilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. CONCLUSIONS: These results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.

Clinical Applicability of Monitoring the Time Interval Between Anesthesia and Electroconvulsive Therapy.

The anesthetic-electroconvulsive therapy (ECT) time interval (time interval elapsed from the beginning of anesthesia injection to the beginning of ECT stimulus) has been reported to have an important impact on seizure quality outcomes, because it is an indirect measure of the anesthetic plasma concentration when the ECT electrical stimulus is administered. We report the importance of the routine monitoring of this time interval in clinical settings, as an additional measure to interpret seizure quality outcomes at each ECT session, to further assist on ECT dosing decisions during the treatment course.

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 (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/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.

Does remifentanil improve ECT seizure quality?

Studies have reported that co-adjuvant remifentanil can enhance electroconvulsive therapy (ECT) seizure quality, putatively by allowing a reduction in the dosage of the main anaesthetic agents, as the latter have anticonvulsant properties. However, whether remifentanil also has direct effects on ECT seizure quality, and by implication, treatment efficacy, is unknown. This is the first study examining the effect of adjuvant remifentanil on ECT seizure quality when the dose of conventional anaesthesia remained unchanged. A total of 96 ECT sessions (from 36 patients) were retrospectively analysed. Subjects received ECT with and without remifentanil (1 µg/kg), while the dose of thiopentone (3-5 mg/kg) or propofol (1-2 mg/kg) was unchanged. Seizure quality indices (time to slow wave activity or TSLOW, amplitude, regularity, stereotypy, post-ictal suppression) and duration were assessed through a structured rating scale by a single trained blinded rater. Linear mixed-effects models with random subject effects analysed the effect of remifentanil on seizure parameters, controlling for other variables that can affect seizure quality or duration. Remifentanil was given in 47.9 % of the ECT sessions. Co-adjuvant remifentanil had no effects on any of the seizure quality parameters analysed [TSLOW (E = -0.21, p > 0.1), amplitude (E = 0.08, p > 0.5), regularity (E = -0.05, p > 0.5), stereotypy (E = -0.02, p > 0.5), suppression (E = -0.3, p > 0.05)] or on seizure duration (E = -0.25, p > 0.1). While adjuvant remifentanil may be a useful strategy for reducing anaesthetic dosage in ECT, present evidence suggests that remifentanil does not have intrinsic properties that enhance ECT seizures.

Pilot Study of Accelerated Low-Frequency Right-Sided Transcranial Magnetic Stimulation for Treatment-Resistant Depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective option for treatment-resistant depression but requires prolonged repeated daily treatments for 4 to 6 weeks. Pilot studies have showed the possibility of accelerating rTMS safely and efficaciously but thus far only investigated high-frequency left-sided rTMS. We sought to investigate the safety and efficacy of accelerated low-frequency right-sided rTMS. METHODS: Our study was an open label accelerated rTMS pilot in 7 treatment-resistant patients (4 unipolar, 3 BP). Accelerated rTMS was given over the right dorsolateral prefrontal cortex at 120% of resting motor threshold at 1 Hz, and 900 pulses were delivered per session. A single rTMS treatment was administered on the first day to test for tolerability, followed by 5 rTMS sessions a day for 2 days, then 7 days of daily rTMS sessions. The total course consisted of 16,200 pulses across 18 sessions given over 10 consecutive weekdays. The primary outcomes of interest were self- and clinician-rated depression scores (BDI-II and MADRS). RESULTS: All patients successfully and safely completed the accelerated rTMS treatment. MADRS scores decreased significantly by the third day of treatment and BDI II scores by the end of the 10-day treatment. No patients achieved response or remission. CONCLUSIONS: Accelerated low-frequency right-sided rTMS was a safe and possibly efficacious treatment for treatment-resistant depression. More research is recommended, including a controlled trial with longer duration of exposure, to establish the efficacy of left- and right-sided accelerated rTMS.

Predicting Retrograde Autobiographical Memory Changes Following Electroconvulsive Therapy: Relationships between Individual, Treatment, and Early Clinical Factors.

BACKGROUND: Loss of personal memories experienced prior to receiving electroconvulsive therapy is common and distressing and in some patients can persist for many months following treatment. Improved understanding of the relationships between individual patient factors, electroconvulsive therapy treatment factors, and clinical indicators measured early in the electroconvulsive therapy course may help clinicians minimize these side effects through better management of the electroconvulsive therapy treatment approach. In this study we examined the associations between the above factors for predicting retrograde autobiographical memory changes following electroconvulsive therapy. METHODS: Seventy-four depressed participants with major depressive disorder were administered electroconvulsive therapy 3 times per week using either a right unilateral or bitemporal electrode placement and brief or ultrabrief pulse width. Verbal fluency and retrograde autobiographical memory (assessed using the Columbia Autobiographical Memory Interview - Short Form) were tested at baseline and after the last electroconvulsive therapy treatment. Time to reorientation was measured immediately following the third and sixth electroconvulsive therapy treatments. RESULTS: Results confirmed the utility of measuring time to reorientation early during the electroconvulsive therapy treatment course as a predictor of greater retrograde amnesia and the importance of assessing baseline cognitive status for identifying patients at greater risk for developing later side effects. With increased number of electroconvulsive therapy treatments, older age was associated with increased time to reorientation. Consistency of verbal fluency performance was moderately correlated with change in Columbia Autobiographical Memory Interview - Short Form scores following right unilateral electroconvulsive therapy. CONCLUSIONS: Electroconvulsive therapy treatment techniques associated with lesser cognitive side effects should be particularly considered for patients with lower baseline cognitive status or older age.

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.

Revisiting frontoparietal montage in electroconvulsive therapy: clinical observations and computer modeling: a future treatment option for unilateral electroconvulsive therapy.

OBJECTIVES: The aim of this study was to compare the clinical effects of frontoparietal electrode placement, an alternative montage for right unilateral electroconvulsive therapy (ECT), with the commonly used temporoparietal montage. METHODS: In a single patient who received alternate treatments with the abovementioned right unilateral montages, within a treatment course of ECT, time-to-reorientation after each treatment and seizure expression were compared. Computer modeling was used to simulate and compare differences in electrical stimulation patterns in key cerebral regions, with the 2 montages. These simulations were done in an anatomically realistic head model recreated from magnetic resonance imaging scans of the patient's head. RESULTS: Time-to-reorientation was shorter after treatment with frontoparietal ECT (mean, 28.3 minutes; SD, 2.9 minutes) than after temporoparietal ECT (mean, 50.0 minutes; SD, 11.5 minutes), suggesting less retrograde memory impairment. Seizure duration and expression were similar for the 2 montages. Computer modeling demonstrated less hippocampal and right inferior frontal cortical stimulation but comparable anterior cingulate cortex stimulation with the frontoparietal montage. CONCLUSIONS: These results, although preliminary, suggest that the frontoparietal montage may result in less memory side effects, but comparable efficacy, to the temporoparietal montage.

Electroconvulsive therapy practice in Catalonia: a survey study comparing data from 1993 and 2010.

OBJECTIVE: The aim of this study was to assess the current use of electroconvulsive therapy (ECT) in Catalonia (Spain) as compared with ECT practice 17 years ago (1993). METHODS: This was a descriptive, cross-sectional study using a structured questionnaire to collect data regarding the use of ECT in Catalan psychiatric units in 2010. A comparative approach was used with respect to previously published data. RESULTS: Data were obtained from 25 of the 27 units (92.6%) surveyed. The ECT was used in 20 facilities (80%, as opposed to 60% in 1993), and in all cases, a brief-pulse device was used. The most commonly used anesthetic was propofol (65%), and most facilities recorded the seizure duration (95%). The ECT was always administered in combination with pharmacologic therapy, and the primary clinical indication was depression. Only 20% of the ECT procedures were performed in the inpatient unit. Written informed consent to administer ECT was obtained in all centers. CONCLUSIONS: The ECT practice in Catalonia has changed since the 1990s, being administered more often, in a more standardized way and across a larger number of psychiatric units. The results indicate considerable consensus with regard to its indications and conditions of application, which comply with current clinical practice guidelines and standards.

Acute bilateral ECT in a depressed patient with a hip-aztreonam-spacer and subsequent maintenance ECT after prosthesis collocation.

ABSTRACT Electroconvulsive Therapy (ECT) has been demonstrated to be a safe and effective treatment for geriatric depression, although its application might be challenging when medical comorbidities exist. The present case reports a 78-year-old man diagnosed with recurrent unipolar major depressive disorder (MDD), who presented with a severe depressive episode with psychotic features (DSM IV). He successfully received a course of bitemporal (BT) ECT with a hip-aztreonam-spacer due to a hip fracture that occurred during hospitalization. This was followed by maintenance ECT (M-ECT) with a recent prosthesis collocation. This particular case illustrates the importance of a multidisciplinary approach in geriatric patients with somatic complications receiving ECT.

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.

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.

Long-term treatment strategies in major depression: a 2-year prospective naturalistic follow-up after successful electroconvulsive therapy.

OBJECTIVE: To describe a 2-year follow-up in a cohort of patients with major depressive disorder treated with pharmacotherapy plus a short-term course of electroconvulsive therapy (ECT) over the index episode. METHODS: This naturalistic study included 127 patients. After remission, the same pharmacotherapy regimen was maintained in all patients, whereas 44 also received continuation/maintenance ECT (C/M-ECT). Demographic and clinical data were reported for patients with pharmacotherapy and patients with pharmacotherapy and C/M-ECT. The clinical course of the disorder was compared two years before and after index episode remission. RESULTS: Continuation/maintenance ECT was more prescribed in men and in those patients with more previous episodes and admissions and higher treatment resistance. Longer duration of index episode and greater number of episodes in the previous 2 years were identified as risk factors for relapse/recurrence. Furthermore, in our sample, a significant improvement of the illness course after remission was observed after successful ECT. CONCLUSION: Both treatments were effective as maintenance strategies for depressive patients who showed complete response to an acute ECT course. According to our observations, pharmacotherapy both alone and plus C/M-ECT may potentially be considered as long-term treatments after successful ECT in patients with severe major depressive disorder.

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry.

OBJECTIVES: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice. METHODS: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps. RESULTS: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine. LIMITATIONS: The KSET has established face and content validity, however it has not been validated against other measures of safety. CONCLUSIONS: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects.