Lee C. Chang

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

OBJECTIVE Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. METHOD This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. CONCLUSIONS Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.

Ketamine safety and tolerability in clinical trials for treatment-resistant depression.

OBJECTIVE Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD. METHOD Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation. RESULTS The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information. CONCLUSIONS In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age=46.2±12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery–Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t=2.3, p=0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.

The Emerging Use of Ketamine for Anesthesia and Sedation in Traumatic Brain Injuries

Traditionally, the use of ketamine for patients with traumatic brain injuries is contraindicated due to the concern of increasing intracranial pressure (ICP). These concerns, however, originated from early studies and case reports that were inadequately controlled and designed. Recently, the concern of using ketamine in these patients has been challenged by a number of published studies demonstrating that the use of ketamine was safe in these patients. This article reviews the current literature in regards to using ketamine in patients with traumatic brain injuries in different clinical settings associated with anesthesia, as well as reviews the potential mechanisms underlying the neuroprotective effects of ketamine. Studies examining the use of ketamine for induction, maintenance, and sedation in patients with TBI have had promising results. The use of ketamine in a controlled ventilation setting and in combination with other sedative agents has demonstrated no increase in ICP. The role of ketamine as a neuroprotective agent in humans remains inconclusive and adequately powered; randomized controlled trials performed in patients undergoing surgery for traumatic brain injury are necessary.

Randomized, controlled trial comparing the effects of anesthesia with propofol, isoflurane, desflurane and sevoflurane on pain after laparoscopic cholecystectomy

BACKGROUND Pain is the primary complaint and the main reason for prolonged recovery after laparoscopic cholecystectomy. The authors hypothesized that patients undergoing laparoscopic cholecystectomy will have less pain four hours after surgery when receiving maintenance of anesthesia with propofol when compared to isoflurane, desflurane, or sevoflurane. METHODS In this prospective, randomized trial, 80 patients scheduled for laparoscopic cholecystectomy were assigned to propofol, isoflurane, desflurane, or sevoflurane for the maintenance of anesthesia. Our primary outcome was pain measured on the numeric analog scale four hours after surgery. We also recorded intraoperative use of opioids as well as analgesic consumption during the first 24h after surgery. RESULTS There was no statistically significant difference in pain scores four hours after surgery (p=0.72). There were also no statistically significant differences in pain scores between treatment groups during the 24h after surgery (p=0.45). Intraoperative use of fentanyl and morphine did not vary significantly among the groups (p=0.21 and 0.24, respectively). There were no differences in total morphine and hydrocodone/APAP use during the first 24h (p=0.61 and 0.53, respectively). CONCLUSION Patients receiving maintenance of general anesthesia with propofol do not have less pain after laparoscopic cholecystectomy when compared to isoflurane, desflurane, or sevoflurane.

Neurocognitive effects following an overnight call shift on faculty anesthesiologists

The impact of sleep deprivation on neurocognitive performance is a significant concern to both the health of patients and to the physicians caring for them, as demonstrated by the Accreditation Council for Graduate Medical Education enforced resident work hours. This study examined the effects of an overnight call at a level 1 trauma hospital on neurocognitive performance of faculty anesthesiologists.

The History of Ketamine Use and Its Clinical Indications

Ketamine, which has a similar chemical structure to phencyclidine, was first administered to humans in 1964 and found to produce a unique effect termed “dissociative anesthesia.” In spite of the potential abuse liability, ketamine remains on the World Health Organization (WHO) Model List of Essential Medicines. It has been approved worldwide as the sole anesthetic agent for certain procedures, for the induction of anesthesia, and as an anesthetic supplement with low-potency agents like nitrous oxide. In addition, ketamine is also used for its analgesic properties in the management of cancer pain, chronic pain, and postoperative pain, among other indications. This chapter describes the history, development, clinical indications, and abuse potential of this agent.