-
1.
Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naïve Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Brinck, ECV, Maisniemi, K, Kankare, J, Tielinen, L, Tarkkila, P, Kontinen, VK
Anesthesia and analgesia. 2021;(1):69-79
Abstract
BACKGROUND Severe pain often accompanies major spine surgery. Opioids are the cornerstone of postoperative pain management but their use can be limited by numerous side effects. Several studies claim that adjuvant treatment with intravenous (IV) ketamine reduces opioid consumption and pain after back surgery. However, the exact role of ketamine for this indication is yet to be elucidated. We compared 2 different doses of S-ketamine with placebo on postoperative analgesic consumption, pain, and adverse events in adult, opioid-naïve patients after lumbar fusion surgery. METHODS One hundred ninety-eight opioid-naïve patients undergoing lumbar spinal fusion surgery were recruited to this double-blind trial and randomly assigned into 3 study groups: Group C (placebo) received a preincisional IV bolus of saline (sodium chloride [NaCl] 0.9%) followed by an intraoperative IV infusion of NaCl 0.9%. Both groups K2 and K10 received a preincisional IV bolus of S-ketamine (0.5 mg/kg); in group K2, this was followed by an intraoperative IV infusion of S-ketamine (0.12 mg/kg/h), while in group K10, it was followed by an intraoperative IV infusion of S-ketamine (0.6 mg/kg/h). Postoperative analgesia was achieved by an IV patient-controlled analgesia (IV PCA) device delivering oxycodone. The primary end point was cumulative oxycodone consumption at 48 hours after surgery. The secondary end points included postoperative pain up to 2 years after surgery, adverse events, and level of sedation and confusion in the immediate postoperative period. RESULTS The median [interquartile range (IQR)] cumulative oxycodone consumption at 48 hours was 154.5 [120] mg for group K2, 160 [109] mg for group K10, and 178.5 [176] mg for group C. The estimated difference was -24 mg between group K2 and group C (97.5% confidence interval [CI], -73.8 to 31.5; P = .170) and -18.5 mg between group K10 and C (97.5% CI, 78.5-29.5; P = .458). There were no significant differences between groups.Postoperative pain scores were significantly lower in both ketamine treatment groups at the fourth postoperative hour but not later during the 2-year study period.The higher ketamine dose was associated with more sedation. Otherwise, differences in the occurrence of adverse events between study groups were nonsignificant. CONCLUSIONS Neither a 0.12 nor a 0.6 mg/kg/h infusion of intraoperative IV S-ketamine was superior to the placebo in reducing oxycodone consumption at 48 hours after lumbar fusion surgery in an opioid-naïve adult study population. Future studies should assess ketamine's feasibility in specific study populations who most benefit from reduced opioid consumption.
-
2.
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.
McIntyre, RS, Rosenblat, JD, Nemeroff, CB, Sanacora, G, Murrough, JW, Berk, M, Brietzke, E, Dodd, S, Gorwood, P, Ho, R, et al
The American journal of psychiatry. 2021;(5):383-399
-
-
Free full text
-
Abstract
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
-
3.
Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.
Kadriu, B, Greenwald, M, Henter, ID, Gilbert, JR, Kraus, C, Park, LT, Zarate, CA
The international journal of neuropsychopharmacology. 2021;(1):8-21
Abstract
BACKGROUND The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
-
4.
Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial.
Bevilacqua, L, Charney, A, Pierce, CR, Richards, SM, Jha, MK, Glasgow, A, Brallier, J, Kirkwood, K, Bagiella, E, Charney, DS, et al
Journal of psychopharmacology (Oxford, England). 2021;(2):124-127
Abstract
Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).
-
5.
Ketamine-facilitated behavioral treatment for cannabis use disorder: A proof of concept study.
Azhari, N, Hu, H, O'Malley, KY, Blocker, ME, Levin, FR, Dakwar, E
The American journal of drug and alcohol abuse. 2021;(1):92-97
Abstract
BACKGROUND Sub-anesthetic ketamine infusions may benefit a range of psychiatric conditions, including alcohol and cocaine use disorders. Currently, there are no effective pharmacological treatments for cannabis use disorder. OBJECTIVES The objective of this uncontrolled proof of concept trial was to test the feasibility, tolerability, and potential therapeutic effects of integrating ketamine infusions with a behavioral platform of motivational enhancement therapy and mindfulness-based relapse prevention in treating cannabis use disorder (CUD). METHODS Eight cannabis-dependent individuals (four female, four male) receiving motivational enhancement therapy and mindfulness-based relapse prevention behavioral treatments completed this single-blind outpatient 6-week study. Participants received either one or two infusions of ketamine (0.71 mg/kg [infusion 1]; 1.41 mg/kg [infusion 2] for non-responders) during the study. Participants self-reported cannabis use (Timeline Follow-Back) and underwent an assessment of confidence in abstaining from using cannabis (Drug-Taking Confidence Questionnaire) at predetermined time points throughout the study. RESULTS Ketamine infusions were well-tolerated and there were no adverse events. Frequency of cannabis use decreased significantly from baseline (B = 5.1, s.e = 0.7) to the week following the first infusion (B = 0.8, s.e = 0.412), and remained reduced at the end of the study (B = 0.5, s.e = 0.3). Participants' confidence in their ability to abstain from cannabis in potentially triggering situations increased significantly from baseline to the end of study. CONCLUSIONS These findings suggest that combining ketamine with behavioral therapy is feasible,tolerable, and potentially helpful, in treating cannabis-dependent individuals.
-
6.
Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review.
Keeler, JL, Treasure, J, Juruena, MF, Kan, C, Himmerich, H
Nutrients. 2021;(11)
Abstract
Anorexia nervosa (AN) is a highly complex disorder to treat, especially in severe and enduring cases. Whilst the precise aetiology of the disorder is uncertain, malnutrition and weight loss can contribute to reductions in grey and white matter of the brain, impairments in neuroplasticity and neurogenesis and difficulties with cognitive flexibility, memory and learning. Depression is highly comorbid in AN and may be a barrier to recovery. However, traditional antidepressants are often ineffective in alleviating depressive symptoms in underweight patients with AN. There is an urgent need for new treatment approaches for AN. This review gives a conceptual overview for the treatment of AN with ketamine. Ketamine has rapid antidepressant effects, which are hypothesised to occur via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis. This article provides an overview of the use of ketamine for common psychiatric comorbidities of AN and discusses particular safety concerns and side effects. Potential avenues for future research and specific methodological considerations are explored. Overall, there appears to be ample theoretical background, via several potential mechanisms, that warrant the exploration of ketamine as a treatment for adults with AN.
-
7.
Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam.
Forsyth, A, McMillan, R, Campbell, D, Malpas, G, Maxwell, E, Sleigh, J, Dukart, J, Hipp, J, Muthukumaraswamy, SD
Human brain mapping. 2020;(6):1472-1494
-
-
Free full text
-
Abstract
The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood-oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo-controlled, three-way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting-state networks. Independent components analysis (ICA)-denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross-modal comparisons of pharmacologically-modulated functional connectivity.
-
8.
Ketamine in seizure management and future pharmacogenomic considerations.
Borsato, GS, Siegel, JL, Rose, MQ, Ojard, M, Feyissa, AM, Quinones-Hinojosa, A, Jackson, DA, Rogers, ER, Freeman, WD
The pharmacogenomics journal. 2020;(3):351-354
Abstract
Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.
-
9.
Neuronal glutamatergic changes and peripheral markers of cytoskeleton dynamics change synchronically 24 h after sub-anaesthetic dose of ketamine in healthy subjects.
Colic, L, McDonnell, C, Li, M, Woelfer, M, Liebe, T, Kretzschmar, M, Speck, O, Schott, BH, Bianchi, M, Walter, M
Behavioural brain research. 2019;:312-319
Abstract
Ketamine acts as a rapid-acting antidepressant by restoring glutamatergic deficits and activating synaptic plasticity processes, with peak activity 24 h after infusion. Microtubule dynamics are known to play a key role in modulation of cytoskeleton and synaptic plasticity, as well as in signalling events in peripheral blood cells. Here, we correlated ketamine-induced change in glutamate/creatinine (Glu/Cr) levels in the pregenual anterior cingulate cortex (pgACC) with peripheral markers of microtubule dynamics, namely acetylated α-tubulin (Acet-Tub), with particular attention to gender specificity. Eighty healthy controls (age = 25.89 ± 5.29, 33 women) were administered intravenous infusion of either ketamine (0.5 mg/kg) or placebo (saline). Blood samples were obtained at baseline and 24 h after infusion and plasma levels of Acet-Tub and transferrin (TRF; loading control) were measured via infrared western blotting. Glu/Cr levels were measured via high-field (7 T) proton magnetic resonance spectroscopy [1H-MRS] in the pgACC at the same time points. Gender differences were observed in baseline Acet-Tub/TRF levels (p < 0.001), and an interaction of time by treatment by gender (F = 5.13, p = 0.027) was found, with a significant increase in Acet-Tub/TRF for ketamine group in females only (p = 0.038). Ketamine-induced gender-independent Glu/Cr changes at 24 h (F(1, 69) = 4.08, p = 0.047), and changes in the pgACC were negatively correlated with the Acet-Tub/TRF expression (r= -0.464, p = 0.010) in the ketamine group, in which, separated by sex, only women showed significant correlation. Our findings indicate a temporal association between changes in central ketamine-induced glutamatergic effects and peripheral markers of cytoskeleton reorganization, particularly in females.
-
10.
The effects of ketamine and lidocaine on free radical production after tourniquet-induced ischemia-reperfusion injury in adults.
Peker, K, Ökesli, S, Kıyıcı, A, Deyişli, C
Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES. 2019;(2):111-117
Abstract
BACKGROUND The primary aim of this study was to compare the effects of a small-dose infusion of 2 antioxidant agents, ketamine and lidocaine, on ischemia-reperfusion injury (IRI) in patients undergoing elective lower limb surgery. Ischemia-modified albumin (IMA), lactate, and blood gas levels were all measured and assessed. METHODS A total of 100 patients who underwent lower extremity surgery were randomized into 3 groups. After spinal anesthesia, the ketamine group (Group K, n=33) was given a ketamine infusion, a lidocaine infusion was administered to the lidocaine group (Group L, n=33), and in the control group (Group C), 0.9% a sodium chloride infusion was performed. Blood samples were obtained for IMA analysis before anesthetic administration (baseline), at 30 minutes of tourniquet inflation (ischemia), and 15 minutes after tourniquet deflation (reperfusion). Arterial blood gas measurements were determined before anesthetic administration and 15 minutes after tourniquet deflation. RESULTS The lactate and IMA levels at reperfusion were significantly lower in both the ketamine group and the lidocaine group when compared with the control group. CONCLUSION The administration of both ketamine and lidocaine infusions significantly decreased skeletal muscle IRI-related high lactate and IMA levels. These results suggest the possibility of the clinical application of ketamine or lidocaine infusions in cases of skeletal muscle-related IRI.