Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Antenatal depression risk under the NSW SAFE START Strategic Policy: Who is missing out on universal screening?

AIM: To examine antenatal depression risk screening coverage under the NSW SAFE START Strategic Policy and to explore maternal and sociodemographic factors associated with under-screening. METHODS: Completion rates for the Edinburgh Depression Scale (EDS) were examined in a retrospective dataset of routinely collected antenatal care data including all women who birthed at public health facilities in Sydney Local Health District from 1 October 2019 to 6 August 2020. Potential sociodemographic/clinical factors associated with under-screening were identified using univariate and multivariate logistic regression. Free-text responses regarding reasons for EDS non-completion were examined using qualitative thematic analysis techniques. RESULTS: A total of 4810 women (96.6%) in our sample (N = 4980) completed antenatal EDS screening; only 170 (3.4%) were not screened or lacked data to indicate that screening had occurred. Multivariate logistic regression analyses showed that women under certain models of antenatal care (public hospital care, private midwife/obstetrician or no formal care), non-English speaking women who required an interpreter, and women whose smoking status during pregnancy was unknown had a higher odds of missing screening. The reasons for EDS non-completion indicated in the electronic medical record revealed language and time/practical constraints to be the most commonly-reported barriers. CONCLUSIONS: Antenatal EDS screening coverage was high in this sample. Refresher training for staff involved can emphasise the need to ensure appropriate screening for women who access shared care in external services (particularly private obstetric care). Additionally, at the service level, improved access to interpreter services and foreign language resources may help minimise EDS under-screening for culturally and linguistically diverse families.

Impact on Electroconvulsive Therapy Services, Including Patient Relapse and Death, During the COVID-19 Pandemic: Quantitative Results From a Multinational Survey.

OBJECTIVES: Electroconvulsive therapy (ECT) is important in the management of major, life-threatening, and treatment-resistant psychiatric illness. The COVID-19 pandemic has significantly disrupted ECT services. The need for new infection control measures, staff redeployment and shortages, and the perception that ECT is as an "elective" procedure have caused changes to, and reductions in, ECT delivery. The aim of this study was to explore the impact of COVID-19 on ECT services, staff, and patients globally. METHODS: Data were collected using an electronic, mixed-methods, cross-sectional survey. The survey was open from March to November 2021. Clinical directors in ECT services, their delegates, and anesthetists were asked to participate. Quantitative findings are reported. RESULTS: One hundred and twelve participants worldwide completed the survey. The study identified significant impacts on services, staff, and patients. Importantly, most participants (57.8%; n = 63) reported their services made at least 1 change to ECT delivery. More than three-quarters (81.0%; n = 73) reported that their service had identified at least 1 patient who could not access ECT. More than two-thirds (71.4%; n = 67) reported that their service identified patients who experienced a relapse in their psychiatric illness due to lack of ECT access. Six participants (7.6%) reported that their service had identified at least 1 patient who died, by suicide or other means, due to lack of ECT access. CONCLUSIONS: All ECT practices surveyed were impacted by COVID-19 with decreases in capacity, staffing, changes in workflow, and personal protective equipment requirements with relatively little change to ECT technique. Lack of access to ECT resulted in significant morbidity and mortality, including suicide, internationally. This is the first multisite, international survey to explore the impacts of COVID-19 on ECT services, staff, and patients.

"ECT should never stop": Exploring the experiences and recommendations of ECT clinical directors and anesthetists about ECT during the COVID-19 pandemic.

Electroconvulsive therapy (ECT) is an effective treatment option for severe, treatment-resistant, and life-threating psychiatric illness. The COVID-19 pandemic has significantly disrupted ECT services. Services across North America, Europe, and Australia have reported decreased ECT delivery, and changes in the ways ECT is delivered. This study aimed to identify the impacts of COVID-19 on ECT services globally by exploring clinicians' experiences about ECT during the pandemic, and their recommendations for reducing the negative impacts of the pandemic. Data were collected using an electronic, cross-sectional survey, which included elicitation of free-text responses. The survey was open from March to November 2021. Clinical directors in ECT services, their delegates, and anesthetists were invited to participate. This paper reports the qualitative analysis of responses provided. Fifty-two participants provided qualitative response/s; 74.5% were clinical directors or their delegates, and 25.5% were anesthetists. Greater than one-third of participants were from Australia/New Zealand, and there was also representation from North America, Europe, and the UK. Participants' responses were detailed, averaging 43 words. Three themes were identified: (1) Service provision, about the importance of ECT services continuing during the pandemic, (2) Preparedness, through guidelines and environmental design, and (3) Personal protection, about strategies to increase staff safety. This is the first multi-site, international study to document the experiences and recommendations of ECT clinical directors and anesthetists about the effect of COVID-19 on ECT practice. The findings inform evidence-based practice, and ensure people with major psychiatric illnesses continue to receive ECT during the pandemic.

The Impact of COVID-19 on Electroconvulsive Therapy: A Multisite, Retrospective Study From the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments Network.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has led to reported change in electroconvulsive therapy (ECT) services worldwide. However, minimal data have been published demonstrating tangible changes across multiple ECT centers. This article aimed to examine changes in ECT patients and ECT service delivery during the pandemic. METHODS: We retrospectively assessed data collected on ECT patients within the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments (CARE) Network during a 3-month period starting at the first COVID-19 restrictions in 2020 and compared data with predicted values based on the corresponding 3-month period in 2019. Mixed-effects repeated-measures analyses examined differences in the predicted and actual number of acute ECT courses started and the total number of acute ECT treatments given in 2020. Sociodemographic, clinical, treatment factors, and ECT service delivery factors were compared for 2020 and 2019. RESULTS: Four Australian and 1 Singaporean site participated in the study. There were no significant differences between the predicted and actual number of acute ECT courses and total number of acute ECT treatments administered in 2020. During 2020, there were statistically significant increases in the proportion of patients requiring ECT under substitute consent and receiving ECT for urgent reasons compared with 2019. CONCLUSIONS: This multisite empirical study is among the first that supports anecdotal reports of changes in the triaging and delivery of ECT during COVID-19. Results suggest that ECT was prioritized for the most severely ill patients. Further data assessing the impacts of COVID-19 on ECT are needed.

Ketamine treatment for depression: A model of care.

OBJECTIVE: Ketamine and related compounds are emerging as rapidly acting therapies for treatment-resistant depression. Ketamine differs from standard antidepressants in its speed of action, specific acute and cumulative side effects, risk of dependence and regulatory requirements. However, there is currently little guidance offering translation from research studies into clinical practice. We therefore detail a comprehensive model of care for ketamine treatment of depression. METHOD: We formulated a set of policies and procedures for a 'compassionate use' ketamine programme that developed out of our clinical research in ketamine. These policies and procedures were formulated into a detailed model of care. RESULTS: The current Australian and New Zealand regulatory frameworks and professional bodies' recommendations regarding ketamine are detailed along with clinical governance and infrastructure considerations. We next describe a four-step model comprising initial assessment, pre-treatment, treatment and post-treatment phases. The model comprises thorough psychiatric and medical assessments examining patient suitability, a rigorous consenting process and structured safety monitoring across an acute treatment course or maintenance therapy. Our ketamine dose-titration method is detailed allowing flexible dosing of patients across a treatment course enabling individualised treatment. CONCLUSION: The model of care aims to bridge the gap between efficacy studies and clinical care outside of research settings as ketamine and related compounds become increasingly important therapies for treatment-resistant depression.

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.

Comparison of Site Localization Techniques for Brain Stimulation.

OBJECTIVES: The dorsolateral prefrontal cortex (DLPFC) is a commonly targeted site using noninvasive brain stimulation techniques. Methods used to localize this site commonly rely on the International 10-20 electroencephalography (EEG) system, including elastic EEG caps, which stretch to accommodate varying head sizes, as well as the Beam F3 algorithm, which uses scalp measurements to calculate the location of the DLPFC. Both methods have been validated against magnetic resonance imaging-based DLPFC localization and are regularly used in research centers and clinics, but an in vivo comparison of reliability has not yet been conducted. This study examines whether Beam F3 and EEG cap methods differ in DLPFC localization, when applied by different practitioners (measurers) on a range of subjects. Further, whether measurer experience or subject head characteristics influence localization. METHODS: Measurers (n = 5) of varying levels of experience identified the location of the left DLFPC on subjects (n = 6) with varying head sizes, using both Beam F3 and EEG cap methods. An independent assessor recorded the measurers' placements along the anterior-posterior and medial-lateral planes. Values were normalized to the subjects' mean nasion-inion and tragus-tragus distances and examined using a mixed effects repeated measures analysis. RESULTS: The Beam F3 method resulted in significantly more anterior placements (~11.5 mm) compared with the EEG cap. Subjects with smaller head sizes had more anterior placements, compared with medium and large heads, regardless of the method used. There was no significant difference between methods along the medial-lateral plane. Measurer experience did not significantly influence DLPFC localization. CONCLUSIONS: Beam F3 and EEG cap methods resulted in similar DLPFC placements, with a small difference along the anterior-posterior plane. Measurer experience did not affect either method, suggesting that 2 weeks of training is sufficient to achieve competency. Training and reliability of DLPFC placement therefore do not represent substantial barriers to application of either method. Special care should be taken with subjects with small heads as both methods resulted in more anterior DLPFC placements.

The impact of chronic fluoxetine on conditioned fear expression and hippocampal FGF2 in rats: Short- and long-term effects.

Phenotypic differences in conditioned fear expression may be a marker of vulnerability to the development of anxiety disorders. Hippocampal FGF2 correlates negatively with conditioned fear expression, and antidepressants, the first-line pharmacological treatment for anxiety, increase hippocampal FGF2. In the present study, we assessed whether treatment with the selective serotonin reuptake inhibitor fluoxetine reduces conditioned fear expression in rats that naturally express lower (Low fear) or higher (High fear) levels of fear following a single-trial conditioning session. Experiment 1 demonstrated that phenotypic differences in fear expression were highly stable over a two-week interval. Experiment 2 demonstrated that two weeks of fluoxetine treatment (administered via drinking water) reduced conditioned fear expression in both Low and High fear rats. Experiment 3 demonstrated that two weeks of fluoxetine reduced conditioned fear expression even when treatment commenced two weeks after fear conditioning, but not when conditioned fear was assessed following a two-week drug-free washout period. Additionally, fluoxetine increased hippocampal FGF2 levels relative to vehicle-treated rats, but only when measured immediately after fluoxetine treatment, and not two weeks after treatment termination. Together, these results provide further indirect evidence that endogenous hippocampal FGF2 may mediate individual differences in conditioned fear expression. They also suggest that fluoxetine may be effective in reducing conditioned fear expression in both vulnerable and resilient populations when administered immediately, or sometime after, aversive experiences, but these effects do not persist once treatment is terminated.

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.