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.

Can the Addition of Maintenance Electroconvulsive Therapy to Pharmacotherapy Improve Relapse Prevention in Severe Major Depressive Disorder? A Randomized Controlled Trial.

Few systematic evaluations have been performed of the efficacy of electroconvulsive therapy (ECT) as a relapse prevention strategy in major depressive disorder (MDD). This is a single-blind, multicenter, randomized controlled trial to compare the efficacy and tolerability of pharmacotherapy plus maintenance ECT (M-Pharm/ECT) versus pharmacotherapy alone (M-Pharm) in the prevention of MDD relapse. Subjects with MDD who had remitted with bilateral acute ECT (n = 37) were randomly assigned to receive M-Pharm/ECT (n = 19, 14 treatments) or M-Pharm (n = 18) for nine months. The subjects were followed up for 15 months. The main outcome was relapse of depression, defined as a score of 18 or more on the Hamilton Depression Rating Scale. At nine months, 35% of the subjects treated with M-Pharm/ECT relapsed as compared with 61% of the patients treated with M-Pharm. No statistically significant differences between groups were indicated by either Kaplan-Meier or Cox proportional hazards regression analyses. The subjects without psychotic features were at higher risk of relapse. There were no statistically significant differences in the MMSE scores of the two groups at the end of the study. Further studies are needed to better define the indications for M-ECT in order to improve its efficacy as a relapse prevention strategy.

Development of the Ketamine Side Effect Tool (KSET).

BACKGROUND: Currently, no specific, systematic assessment tool for the monitoring and reporting of ketamine-related side effects exists. Our aim was to develop a comprehensive Ketamine Side Effect Tool (KSET) to capture acute and longer-term side effects associated with repeated ketamine treatments. METHODS: Informed by systematic review data and clinical research, we drafted a list of the most commonly reported side effects. Face and content validation were obtained via feedback from collaborators with expertise in psychiatry and anaesthetics, clinical trial piloting and a modified Delphi Technique involving ten international experts. RESULTS: The final version consisted of four forms that collect information at time points: screening, baseline, immediately after a single treatment, and longer-term follow-up. Instructions were developed to guide users and promote consistent utilisation. LIMITATIONS: Further evaluation of feasibility, construct validity and reliability is required, and is planned across multiple international sites. CONCLUSIONS: The structured Ketamine Side Effect Tool (KSET) was developed, with confirmation of content and face validity via a Delphi consensus process. This tool is timely, given the paucity of data regarding ketamine's safety, tolerability and abuse potential over the longer term, and its recent adoption internationally as a clinical treatment for depression. Although based on data from depression studies, the KSET has potential applicability for ketamine (or derivatives) used in other medical disorders, including chronic pain. We recommend its utilisation for both research and clinical scenarios, including data registries.

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.

Electroconvulsive practice in Singapore: a cross-sectional national survey.

INTRODUCTION: The use of electroconvulsive therapy (ECT) in Singapore dates back to 1947. However, there is little local information on the clinical practice of ECT and its standards. We aimed to conduct a comprehensive national survey of ECT practice in Singapore. METHODS: A cross-sectional structured questionnaire assessing the types of ECT (e.g. electrode placement, stimulus parameters), indications, anaesthetic technique, dosing methods, monitoring of outcomes and credentialing was sent in 2015 to all ECT centres in Singapore via email to collect qualitative and quantitative data regarding ECT. RESULTS: Data was obtained from all ECT centres (n = 6), which represented that ECT was available in 23.1% of all hospitals and 50.0% of all psychiatric specialist centres. The rate of ECT was 5.89 treatments per 10,000 residents per year, and each patient received an average of 5.4 ECT per course. Only 7.0% of ECT was administered for continuation/maintenance ECT. The most common indication for ECT was depression in 5 (83.3%) out of six centres, with schizophrenia being the second most common. In 5 (83.3%) out of six centres, ECT was brief (0.5 ms) bitemporal ECT with age-based dosing, and 93.0% of the sessions were conducted in an inpatient setting. All ECT was conducted under general anaesthesia, with propofol (66.7%) being the most common type of anaesthetic used. CONCLUSION: The practice of ECT in Singapore was highly uniform. The rates and indications for ECT were consistent with those of other developed countries, with greater use of ECT for schizophrenia. Future advances for ECT in Singapore include the use of individualised dosing based on empirical seizure threshold titration, expanded electrode placements and increased utilisation of continuation/maintenance ECT.

The anaesthetic-ECT time interval with thiopentone-Impact on seizure quality.

BACKGROUND: The time between anaesthetic induction and ECT stimulus administration has been hypothesised to significantly impact ictal EEG quality. In this study, our aim was to examine the effect of the time interval between anaesthetic induction and the ECT stimulus for ictal seizure quality in ECT sessions utilising thiopentone anaesthesia. METHODS: 413 EEG traces from 42 patients, collected retrospectively, were manually rated using a quantitative-qualitative structured rating scale (indices including seizure amplitude, regularity, post-ictal suppression and general seizure quality). Linear Mixed Effects Models were used to analyse the effect of the anaesthetic-ECT time interval on seizure quality indices, seizure duration and orientation scores after ECT, controlling for patient and ECT treatment factors. RESULTS: The anaesthetic-ECT time interval had a significant impact on ictal EEG quality indices (p < 0.05), with longer times producing higher quality seizures. Seizure duration and orientation scores after ECT were not significantly influenced by the anaesthetic-ECT time interval. Age, anaesthetic dose, ECT type and ECT treatment number also had a significant impact on measures of seizure quality (p < 0.05). LIMITATIONS: The effect of ventilation technique was not explicitly measured. Only manual ratings of ictal quality were analysed. CONCLUSIONS: The time between anaesthetic induction and ECT stimulus administration has a significant impact on the ictal EEG seizure quality observed, with thiopentone anaesthetic. These results are consistent with prior findings with propofol anaesthesia, and suggest a need for routine clinical monitoring of this time interval. This variable warrants consideration when interpreting ictal EEGs, which often informs subsequent dosing decisions.

Estimating The Quality of Electroconvulsive Therapy Induced Seizures Using Decision Tree and Fuzzy Inference System Classifiers.

Electroconvulsive therapy (ECT) is an effective and widely used treatment for major depressive disorder, in which a brief electric current is passed through the brain to trigger a brief seizure. This study aims to identify seizure quality rating by utilizing a set of seizure parameters. We used 750 ECT EEG recordings in this experiment. Four seizure related parameters, (time of slowing, regularity, stereotypy and post-ictal suppression) are used as inputs to two classifiers, decision tree and fuzzy inference system (FIS), to predict seizure quality ratings. The two classifiers produced encouraging results with error rate of 0.31 and 0.25 for FIS and decision tree, respectively. The classification results show that the four seizure parameters provide relevant information about the rating of seizure quality. Automatic scoring of seizure quality may be beneficial to clinicians working in this field.

Early improvement as a predictor of final remission in major depressive disorder: New insights in electroconvulsive therapy.

BACKGROUND: Early improvement to antidepressant drugs predicts remission, but the predictive value of early improvement to electroconvulsive therapy (ECT) is still unclear. The main aim of this study was to determine the optimal definition of early improvement in the treatment of major depressive disorder (MDD) with ECT, by analyzing its value as a predictor of remission. METHODS: A naturalistic study was conducted in 87 adult MDD patients treated with acute ECT. ROC curves were generated to identify the best time point (week 1 or 2 of treatment) predicted remission. Sensibility, specificity, and predictive values were calculated for several definitions of early improvement previously proposed in the literature (20%, 25%, 30%, and 35%). Complementary, time to remission was analyzed and a logistic regression model was performed to further characterize the impact of the optimal definition of early improvement on remission while adjusting for other clinically relevant variables. RESULTS: A 30% reduction in the HAM-D score after 2 weeks was identified as the optimal definition of early improvement, with acceptable sensitivity (76%), and specificity (67%). Complementary analyses provided further support for this definition showing a shorter time to remission and a significant effect adjusted for the rest of variables. LIMITATIONS: Relatively small sample size, ECT restricted to brief bilateral treatment. CONCLUSIONS: Early improvement, defined as a 30% of reduction in the HAM-D21 score at week 2, is a good predictor of remission in MDD patients treated with bilateral ECT, with potential clinical impact. Lack of early improvement could indicate a need for further changes in treatment strategies.

Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial.

BACKGROUND: Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments. METHODS: This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment. RESULTS: Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups. CONCLUSIONS: IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.

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.

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.

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.

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.

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.

Treatment-emergent mania/hypomania during antidepressant treatment with transcranial direct current stimulation (tDCS): A systematic review and meta-analysis.

BACKGROUND: Treatment-emergent mania/hypomania (TEM) is a possible adverse effect of pharmacological and non-pharmacological antidepressant treatments. OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the risk of TEM in depressed patients during randomized, sham-controlled trials (RCTs). DATA SOURCES: Medline database, from the first date available to August 12, 2016. RESULTS: From 283 references, 10 RCTs were identified. Only 3 of them described TEM. In active and sham groups, respectively, only 8 of 226 (3.5%) and 1 of 190 (0.5%) participants presented TEM. This difference was not statistically significant (OR = 1.79, 95% CI = 0.6 to 5.32). There were also five additional reports of TEM in participants not on RCTs. No risk factors for TEM were identified. LIMITATIONS: Low number of studies and TEM reports. CONCLUSION: Despite previous reports, active vs. sham tDCS was not associated with a significantly greater number of TEM episodes.

The use of ketamine in ECT anaesthesia: A systematic review and critical commentary on efficacy, cognitive, safety and seizure outcomes.

OBJECTIVES: This review will discuss ECT efficacy and cognitive outcomes when using ketamine as an ECT anaesthetic compared to other anaesthetics, taking into account important moderator variables that have often not been considered to date. It will also include information on safety and other ECT outcomes (seizure threshold and quality). METHODS: A systematic search through MEDLINE, PubMed, PsychINFO, Cochrane Databases and reference lists from retrieved articles was performed. Search terms were: "ketamine" and "Electroconvulsive Therapy", from 1995 to September 2016. Meta-analyses, randomised controlled trials, open-label and retrospective studies published in English of depressed samples receiving ECT with ketamine anaesthesia were included (n = 24). RESULTS: Studies were heterogeneous in the clinical populations included and ECT treatment and anaesthetic methods. Frequently, studies did not report on ECT factors (i.e., pulse-width, treatment schedule). Findings regarding efficacy were mixed. Tolerance from repeated use may explain why several studies found that ketamine enhanced efficacy early in the ECT course but not at the end. The majority of studies did not comprehensively examine cognition and adverse effects were not systematically studied. Only a minority of the studies reported on seizure threshold and expression. CONCLUSIONS: The routine use of ketamine anaesthesia for ECT in clinical settings cannot yet be recommended based on published data. Larger randomised controlled trials, taking into account moderator variables, specifically reporting on ECT parameters and systematically assessing outcomes are encouraged.

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.