Study protocol for Ketamine as an adjunctive therapy for major depression (2): a randomised controlled trial (KARMA-Dep [2]).

BACKGROUND: Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine's antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator. METHODS: This protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under "real world" conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness. DISCUSSION: There is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression. TRIAL REGISTRATION: EudraCT 2019-003109-92. Registered 2 October 2019. CLINICALTRIALS: gov NCT04939649. Registered 25 June 2021.

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial).

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response.  Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression.  The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick's Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up.  Results: In total, 1581 admissions to St Patrick's Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Ketamine Versus Midazolam for Depression Relapse Prevention Following Successful Electroconvulsive Therapy: A Randomized Controlled Pilot Trial.

OBJECTIVE: Depression relapse after electroconvulsive therapy (ECT) is common (40% at 6 months). Ketamine has a robust antidepressant effect, but there are no reported studies of ketamine for depression relapse prevention. This pilot trial (NCT02414932) was designed to assess feasibility of the proposed trial protocol, including examining reasons for nonrecruitment, nonrandomization, and dropout. METHODS: Patients with unipolar depression referred for ECT were monitored weekly for therapeutic response, using the 24-item Hamilton Rating Scale for Depression (monitoring phase). Those who met standard response criteria were invited to be randomized to a course of 4 once-weekly infusions of ketamine (0.5 mg/kg) or the active comparator, midazolam (0.045 mg/kg), over 40 minutes to examine trial processes (treatment phase). Participants were followed up for 6 months after ECT to assess for relapse. RESULTS: One hundred seventy-five referrals were screened over 18 months, and 68% of eligible participants (n = 43) were recruited to the monitoring phase; 60.5% of participants met ECT response criteria (n = 26), but only 26% (6) of these consented to take part in the treatment phase. These were randomized (3 to ketamine and 3 to midazolam), and no participant completed the 4-week treatment protocol. Information was gathered on reasons for nonrecruitment, nonrandomization, and dropout, which included practical aspects of infusions and lack of interest in further treatment after response to ECT. CONCLUSIONS: The proposed treatment protocol is not suitable for a definitive trial in our center. Information collected on reasons for dropout may inform future clinical trials of intravenous ketamine. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02414932.

Epistaxis during nasotracheal intubation: a randomized trial of the Parker Flex-Tip™ nasal endotracheal tube with a posterior facing bevel versus a standard nasal RAE endotracheal tube.

PURPOSE: Nasotracheal intubation is a widely performed technique to facilitate anesthesia induction during oral, dental, and maxillofacial surgeries. The technique poses several risks not encountered with oropharyngeal intubation, most commonly epistaxis due to nasal mucosal abrasion. The purpose of this study was to test whether the use of the Parker Flex-Tip™ (PFT) nasal endotracheal tube (ETT) with a posterior facing bevel reduces epistaxis when compared with the standard nasal RAE ETT with a leftward facing bevel. METHODS: Sixty American Society of Anesthesiologists physical status I and II patients undergoing oral or maxillofacial surgery with nasotracheal intubation were recruited. Patients were randomized to either a standard nasal RAE ETT or a PFT nasal ETT. The ETT was thermosoftened and lubricated for both study groups prior to insertion, and the size of the tube was chosen at the discretion of the attending anesthesiologist. The primary outcome was the incidence of epistaxis, with a secondary outcome of epistaxis severity (scored as none, mild, moderate, or severe). An investigator measured both outcomes five minutes after intubation was completed. RESULTS: Mild or moderate epistaxis was experienced by 22 of 30 (73%) patients in the PFT group compared with 21 of 30 (70%) patients in the standard nasal RAE ETT group (absolute risk reduction, 3%; 95% confidence interval, -19 to 25; P = 0.78). There were no occurrences of severe epistaxis in either group. CONCLUSION: There was no difference in the incidence or severity of epistaxis following nasal intubation using the Parker Flex-Tip nasal ETT when compared with a standard nasal RAE ETT. This trial was registered at ClinicalTrials.gov, identifier: NCT02315677.

Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial).

BACKGROUND: Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease. Unfortunately, about 30 % of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 45-60 % of such treatment-resistant patients will remit with electroconvulsive therapy (ECT). However, relapse rates are high following ECT-38 % after 6 months. There is a need for better relapse prevention strategies. One possibility is to use ketamine, a competitive glutamate receptor antagonist used for anaesthesia. A recent paradigm shift in treating depression and understanding its biology has been the finding that ketamine has a robust, rapid-onset, though short-lived, antidepressant effect that is possibly mediated through neuroplastic effects. However, ketamine has not previously been reported on for relapse prevention. METHODS/DESIGN: The main objective of this study is to conduct a randomised controlled pilot trial (n = 40) of a 4-week course of once-weekly ketamine infusions for relapse prevention following ECT for depression to assess trial procedures that will inform a future definitive trial. Participants with unipolar depression will be recruited prior to commencing ECT and be assessed weekly during the ECT course using the primary clinical outcome, the 24-item Hamilton Rating Scale for Depression (HRSD-24). Those who meet standard response criteria will be invited, on completing ECT, to be randomised in a 1:1 ratio to a course of four once-weekly infusions of ketamine or an active comparator midazolam, which mimics some of the effects of ketamine and may improve blinding over inactive placebo. Participants will be followed up over 6 months using the HRSD-24 to assess for relapse. DISCUSSION: This is the first registered trial (NCT02414932, https://clinicaltrials.gov/ct2/show/NCT02414932) of ketamine for depression relapse prevention, an important possible use of this agent. The primary focus of the pilot trial is on feasibility. However, a 95 % confidence interval will be determined for the difference between ketamine and midazolam groups in 6-month relapse rates to help inform a future definitive trial. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT02414932 Secondary Identifying numbers: EudraCT number: 2014-000339-18 Sponsors' Reference, Sponsor: St. Patrick's Mental Health Services: 05/14 Research Ethics Committee Reference, Joint REC of St James' and Tallaght Hospitals, Dublin: 2014-08-19.

Real-time measurement of blood pressure with Nexfin in a patient with thalidomide-related phocomelia.

We report the novel application of photoplethysmographic technology with the Nexfin HD monitor for real-time measurement of blood pressure (BP) in a patient with tetraamelia. The patient was a 58-year-old man with tetraamelia secondary to thalidomide exposure in utero, who presented for surgical excision of a maxillary schwannoma. Because difficulty of cuff use on rudimentary limbs and failure to gain invasive arterial access due to abnormalities of limb vasculature, this population is known to pose some unique challenges for BP measurement. Nexfin may offer an alternative noninvasive method to detect BP in patients with phocomelia during the perioperative period.