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.

Australasian Consensus Statement on the Identification, Prevention, and Management of Hormonal Crises in Patients with Neuroendocrine Neoplasms Undergoing Peptide Receptor Radionuclide Therapy.

Hormonal crises are a rare but increasingly recognized phenomenon following peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine neoplasms (NENs). Due to the paucity of published studies, approaches to the identification, prevention, and management of risk factors are inconsistent between different institutions. This consensus statement aimed to provide guidance for NEN patients undergoing PRRT. Our statement has been created on the basis of clinical demand and concerns regarding the precipitation of hormonal crises. A formal literature review was conducted to identify available studies. A total of 19 Australian and New Zealand experts in the fields of medical oncology, nuclear medicine, anaesthetics, and endocrinology collaborated on this consensus statement. The main focus is on carcinoid crises. Other hormonal crises seen in patients with functional pancreatic NENs are addressed briefly. These recommendations are relevant to PRRT centres internationally and should be tailored to local experience and available resources.

The Potential Impacts of a Digital Preoperative Assessment Service on Appointments, Travel-Related Carbon Dioxide Emissions, and User Experience: Case Study.

BACKGROUND: The National Health Service (NHS) cannot keep up with the demand for operations and procedures. Preoperative assessments can be conducted on the internet to improve efficiency and reduce wait times for operations. MyPreOp is a cloud-based platform where patients can complete preoperative questionnaires. These are reviewed by a nurse who determines whether they need a subsequent face-to-face appointment. OBJECTIVE: The primary objective of this study is to describe the potential impact of MyPreOp (Ultramed Ltd) on the number of face-to-face appointments. The secondary objectives are to examine the time spent on preoperative assessments completed using MyPreOp in NHS Trusts and user ratings of usability and acceptability. METHODS: The study design was a case study service evaluation. Data were collected using the MyPreOp system from 2 NHS Trusts (Guy's and St Thomas' and Royal United Hospitals Bath) and the private BMI Bath Clinic during the 4-month period from September to December 2020. Participants were adults of any age and health status at the participating hospitals who used MyPreOp to complete a preoperative assessment before a scheduled surgery. The primary outcome was the number of face-to-face appointments avoided by patients who used MyPreOp. The investigated secondary outcomes included the length of time spent by nurses completing preoperative assessments, associated travel-related carbon dioxide emissions compared with standard care, and quantitative user feedback. User feedback was assessed at all 3 sites; however, the other outcomes could only be examined in the Royal United Hospitals Bath sample because of data limitations. RESULTS: Data from 2500 participants were included. Half of the assessed patients did not need a further face-to-face appointment and required a median of only 5.3 minutes of nurses' time to review. The reduction in appointments was associated with a small saving of carbon dioxide equivalent emissions (9.05 tons). Patient feedback was generally positive: 79.8% (317/397) of respondents rated MyPreOp as easy or very easy to use, and 85.2% (340/399) thought the overall experience was good or very good. CONCLUSIONS: This evaluation demonstrates the potential benefits of MyPreOp. However, further research using rigorous scientific methodology and a larger sample of NHS Trusts and users is needed to provide strong evidence of MyPreOp's efficacy, usability, and cost-effectiveness.

The Economic Impact on Australian Patients with Neuroendocrine Tumours.

BACKGROUND AND OBJECTIVE: Little is known about the economic burden to patients and families with neuroendocrine tumours (NETs) for medical out-of-pocket expenses and employment decisions. This study was performed to determine the extent and factors influencing the financial consequences of living with NETs and their effect on quality of life. METHODS: We undertook an online cross-sectional survey using a targeted approach and collected Australian Medicare claims data. Validated surveys measured health-related quality of life (EuroQol 5-dimension 5-level [EuroQol-5D-5L]) and financial toxicity (COmprehenSive Financial Toxicity [COST]), supplemented with questions on employment and retirement, insurance and out-of-pocket medical expenses. Generalised linear models were performed to assess determinants of quality of life and out-of-pocket expenses recorded by Medicare. RESULTS: The survey was answered by 204 patients with a mean age of 59 years who were diagnosed on average 5.2 years ago. Self-reported mean costs were 1698 Australian dollars ($A) (standard deviation [SD] $A2132) over 3 months (median $A877) and were highest for medical tests (mean $A376 [17% of total costs], SD $A722), travel-related expenses (mean $A289 [13%], SD $A559), and specialist visits (mean $A225 [10%], SD $A342) ($A1 = $US0.69). Imaging scans, surgery and travel expenses were the most common cost burdens reported by patients. Having private health insurance was the key determinant of higher out-of-pocket costs. Poorer quality of life was significantly associated with higher financial toxicity, not working due to cancer, nausea/diarrhoea, two or more co-morbidities and younger age. CONCLUSIONS: Medical expenses are substantial for some patients with NETs. Quality of life is adversely affected for patients experiencing financial toxicity and avoiding early retirement is an important issue for supportive care services.

Effects of the Anaesthetic-ECT time interval and ventilation rate on seizure quality in electroconvulsive therapy: A prospective randomised trial.

BACKGROUND: The anaesthetic approach adopted in ECT practice has the potential to influence patient outcomes. However, the impact of the time interval between anaesthetic induction and ECT stimulus administration has not been studied prospectively to date. This variable may represent an indirect measure of anaesthetic concentration at the time of stimulation, and therefore may influence the quality of seizures induced. OBJECTIVE: To examine the impact of the anaesthetic to ECT stimulus time interval, and ventilation rate pre-treatment, on ictal seizure quality. METHODS: In a prospective, crossover trial, 54 depressed participants were randomised to variations in anaesthetic technique at four sequential ECT treatment sessions, in a 2 x 2 design: randomisation to a short or long anaesthetic-ECT time interval, and randomisation to normal ventilation or hyperventilation during anaesthetic induction with thiopentone. Ictal EEG data were collected at each study session and assessed by a blinded rater for ictal quality (seizure amplitude, regularity, post-ictal suppression and general seizure quality), using a quantitative-qualitative structured rating scale. Linear mixed effects models were used to analyse the effect of the anaesthetic-ECT time interval, and that of ventilation rate, on seizure quality indices. RESULTS: The anaesthetic-ECT time interval had a significant impact on ictal EEG quality indices (p < 0.01), with longer time intervals producing higher quality seizures. Ventilation rate did not significantly influence quality measures. CONCLUSION: The time between anaesthetic induction and ECT stimulus administration has a significant impact on ictal EEG seizure quality. Conversely, manipulations of ventilation rate did not significantly affect seizure quality. These results suggest the anaesthetic-ECT time interval should be routinely monitored clinically and potentially optimised for maximising seizure quality with ECT.

Defining the Supportive Care Needs and Psychological Morbidity of Patients With Functioning Versus Nonfunctioning Neuroendocrine Tumors: Protocol for a Phase 1 Trial of a Nurse-Led Online and Phone-Based Intervention.

BACKGROUND: Online information resources and support have been demonstrated to positively influence the well-being of people diagnosed with cancer. This has been explored in past literature for more common cancers; however, for rare cancers, such as neuroendocrine tumors (NETs), there are little to no support or resources available. Despite relatively good prognoses, the quality of life (QoL) of patients with NETs is significantly lower compared with samples of mixed cancer patients and the general population. Patients with NETs also typically report unclear and difficult pathways of disease management and treatment, given the heterogeneity of the diagnosis. There is a vital need to improve the availability of disease-specific information for this patient group and provide supportive care that is tailored to the unique needs of the NET patient population. OBJECTIVE: This study described the protocol of a study aimed to better understand the outcomes and experiences of patients diagnosed with NETs and to develop and pilot test a nurse-led online and phone-based intervention that will provide tailored supportive care targeted to NET subgroups (functioning vs nonfunctioning). METHODS: This is a multisite cohort with 3 phases, incorporating both quantitative and qualitative data collection. Phase 1 is a mixed methods prospective cohort study of NET patients identifying differences in patient experiences and priority of needs between NET subgroups. Phase 2 utilizes results from phase 1 to develop an online and nurse-led phone-based intervention. Phase 3 is to pilot test and evaluate the intervention's acceptability, appropriateness, and feasibility. RESULTS: Currently, the project is progressing through phase 1 and has completed recruitment. A total of 138 participants have been recruited to the study. To date, patient-reported outcome data from 123 participants at baseline and 87 participants at 6-month follow-up have been collected. Of these, qualitative data from semistructured interviews from 35 participants have also been obtained. Phase 2 and phase 3 of the project are yet to be completed. CONCLUSIONS: Limited research for patients with NETs suggests that QoL and patient experiences are significantly impaired compared with the general population. Furthermore, past research has failed to delineate how the clinical variability between those with functioning and nonfunctioning NETs impacts patient supportive care needs. This study will improve on the availability of disease-specific information as well as informing the design of a nurse-led online and phone-based supportive care intervention tailored for the unique needs of the NET patient population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14361.

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.

Patient-reported experience of the impact and burden of neuroendocrine tumors: Oceania patient results from a large global survey.

AIM: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' lives, the patient journey is not well documented. The aim of this survey was to identify the impact and burden of NETs from the patient perspective. METHODS: This was a self-reported global survey regarding NET knowledge/awareness, disease impact/management, interaction with medical teams, and desired improvements. One hundred thirty-eight patients (7% of the global study) in the Oceania region answered closed-ended questions using graded descriptors on their experience of living with NETs. RESULTS: The personal lives of patients were negatively impacted by NETs, including overall energy levels (72%, 99/138), emotional health (66%, 91/138), and finances (56%, 77/138). Eighty-one percent (22/27) of patients not currently working stated that their NET was the reason they were not employed. Of those still working, taking days off work (64%, 39/61), working reduced hours (44%, 27/61) and stopping work for a period of time (31%, 19/61) were the most frequently reported outcomes of having a NET. Although most patients felt supported by their medical team (53% [73/138] reported being extremely or very supported by healthcare professionals in general), patients also identified areas for improvement in patient care. Better access to NET-specific treatments (58%, 80/138), more awareness about NETs (58%, 80/138) and materials to help patients better explain their condition (52%, 72/138) were indicated by patients as ways to help them live better with their disease. CONCLUSION: The survey demonstrated a considerable burden of NETs on patients' lives and identified areas for improvements in long-term management.

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).

Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs.

PURPOSE: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' daily lives, the journey of the patient with a NET has rarely been documented, with published data to date being limited to small qualitative studies. NETs are heterogeneous malignancies with nonspecific symptomology, leading to extensive health care use and diagnostic delays that affect survival. A large, international patient survey was conducted to increase understanding of the experience of the patient with a NET and identify unmet needs, with the aim of improving disease awareness and care worldwide. METHODS: An anonymous, self-reported survey was conducted (online or on paper) from February to May 2014, recruiting patients with NETs from > 12 countries as a collaboration between the International Neuroendocrine Cancer Alliance and Novartis Pharmaceuticals. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, NET knowledge/awareness, and sources of information. This article reports the most relevant findings on patient experience with NETs and the impact of NETs on health care system resources. RESULTS: A total of 1,928 patients with NETs participated. A NET diagnosis had a substantially negative impact on patients' personal and work lives. Patients reported delayed diagnosis and extensive NET-related health care resource use. Patients desired improvement in many aspects of NET care, including availability of a wider range of NET-specific treatment options, better access to NET experts or specialist centers, and a more knowledgeable, better-coordinated/-aligned NET medical team. CONCLUSION: This global patient-reported survey demonstrates the considerable burden of NETs with regard to symptoms, work and daily life, and health care resource use, and highlights considerable unmet needs. Further intervention is required to improve the patient experience among those with NETs.

Patient-Reported Experience of Diagnosis, Management, and Burden of Neuroendocrine Tumors: Results From a Large Patient Survey in the United States.

OBJECTIVES: The aim of this survey was to examine the experience of patients with neuroendocrine tumors (NETs) to raise awareness of the NET-related burden and identify unmet needs. Here, we report data from patients in the United States. METHODS: Patients with NETs participated in a 25-minute anonymous survey, conducted primarily online from February to May 2014. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, and NETs knowledge/awareness. RESULTS: Of 1928 patients who participated globally, the largest percentage was from the United States (39%). Approximately 50% of US patients reported being diagnosed with other conditions before receiving their NET diagnosis, which for 34% took 5 years or more. Patients experienced many symptoms on a daily basis as a result of NETs, which had a substantial negative impact on their work and daily lives. Numerous improvements were suggested by patients, including better access to NET-specific treatments and medical teams/centers and better education for the management of disease-related and treatment-related symptoms. CONCLUSIONS: This survey demonstrated the significant burden of NETs on patients' lives and identified key areas for improvement in diagnosis and long-term management, including better access to NET-specific treatments and specialist medical teams/centers.

The Anaesthetic-ECT Time Interval in Electroconvulsive Therapy Practice--Is It Time to Time?

BACKGROUND: Because most common intravenous anaesthetics used in ECT have anticonvulsant properties, their plasma-brain concentration at the time of seizure induction might affect seizure expression. The quality of ECT seizure expression has been repeatedly associated with efficacy outcomes. The time interval between the anaesthetic bolus injection and the ECT stimulus (anaesthetic-ECT time interval) will determine the anaesthetic plasma-brain concentration when the ECT stimulus is administered. OBJECTIVE: The aim of this study was to examine the effect of the anaesthetic-ECT time interval on ECT seizure quality and duration. METHODS: The anaesthetic-ECT time interval was recorded in 771 ECT sessions (84 patients). Right unilateral brief pulse ECT was applied. Anaesthesia given was propofol (1-2 mg/kg) and succinylcholine (0.5-1.0 mg/kg). Seizure quality indices (slow wave onset, amplitude, regularity, stereotypy and post-ictal suppression) and duration were rated through a structured rating scale by a single blinded trained rater. Linear Mixed Effects Models analysed the effect of the anaesthetic-ECT time interval on seizure quality indices, controlling for propofol dose (mg), ECT charge (mC), ECT session number, days between ECT, age (years), initial seizure threshold (mC) and concurrent medication. RESULTS: Longer anaesthetic-ECT time intervals lead to significantly higher quality seizures (p < 0.001 for amplitude, regularity, stereotypy and post-ictal suppression). CONCLUSIONS: These results suggest that the anaesthetic-ECT time interval is an important factor to consider in ECT practice. This time interval should be extended to as long as practically possible to facilitate the production of better quality seizures. Close collaboration between the anaesthetist and the psychiatrist is essential.

Should Nurses Administer Electroconvulsive Therapy?

In England, electroconvulsive therapy (ECT) has been traditionally administered by trainee or consultant psychiatrists with support from nurses. We believe that providing senior nurses, who specialize in ECT, with the appropriate training support to administer ECT will increase the capacity and capability of the team and improve the service for patients.

Pilot dose-response trial of i.v. ketamine in treatment-resistant depression.

OBJECTIVES: Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. METHODS: In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2-5 min, 1 week apart, and one randomly inserted placebo treatment. RESULTS: Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery-Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. CONCLUSIONS: This is the first trial to present dose-response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.