Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

Riva‐Posse, Patricio; Reiff, Collin; Edwards, Johnathan A.; Job, Gregory; Galendez, Gail C.; Garlow, Steven J.; Saah, Tammy; Dunlop, Boadie W.; McDonald, William M.

doi:10.1016/j.jad.2018.02.025

Cited by 46 publications

(37 citation statements)

References 25 publications

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“…Overall, a recent retrospective analysis in individuals who received 684 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) reported that alterations in blood pressure are modest, well tolerated, and clinically insignificant (Riva-Posse et al, 2018).…”

Section: Clinical Effectsmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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Section: Clinical Effectsmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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“…In a recently published study, IV infusion of ketamine (0.5 mg/kg over 40 min) in patients with major depressive disorder was associated with mean systolic BP (SBP) and diastolic BP (DBP) increase by ~ 3 mmHg at peak, 30 min into the infusions, and returned toward baseline levels shortly thereafter [13]. Wan et al [14] reported higher transient BP increases (peak increase of 19.6/13.4 mmHg based on 205 ketamine infusions) [14].…”

Section: Cardiac Safety Assessmentsmentioning

confidence: 99%

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program

et al. 2020

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Background An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). Transient cardiovascular stimulatory effects have been reported with ketamine. Methods Cardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine-treated adults with TRD in six trials (five double-blind, placebo-controlled (486 placebo-treated patients); one open-label) of 4-52 weeks' duration. Patients with established cardiovascular disease, including uncontrolled hypertension (> 140/> 90 mmHg), history of hypertensive crisis, or clinically significant electrocardiogram (ECG) abnormalities, were excluded from enrollment. Effects on cardiac repolarization were assessed in a phase I randomized, positive-and activecontrolled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated. Results Adverse events related to increased BP were reported in 12.8% of all esketamine-treated patients (in double-blind trials: esketamine/antidepressant 11.6% vs. antidepressant/placebo 3.9%; OR 3.2 [1.9-5.8]). Among the patients without a history of hypertension, new antihypertensive medication was initiated by 2.1% (6/280) of patients in the esketamine/antidepressant group versus 1.2% (2/171) of patients in the antidepressant/placebo group, in the double-blinded studies. Adverse events related to abnormal heart rate were reported in 3.0% of all esketamine-treated patients (in double-blind trials: 1.6% vs. 0.8%; OR 1.9 [0.5-8.6]). Overall, three cardiovascular adverse events related to BP increase were reported as serious and severe, and there was one fatal event considered unrelated (acute cardiac failure). BP increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h postdose. In two studies (4-week duration, age 18-64 years), the largest mean maximum systolic/diastolic postdose BP increases were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo, and in a short-term elderly study (age ≥ 65 years) were 16.0/9.5 and 11.1/6.8 mmHg, respectively. Across studies/study phases, < 2% of patients discontinued esketamine due to adverse events of increased BP and tachycardia. No clinically relevant effect on ECG parameters was observed. Therapeutic and supratherapeutic doses of esketamine did not prolong the QTcF (QT corrected by Fridericia's equation) interval (baseline-corrected values of − 2.02 to 2.16 ms, and − 3.51 to 4.89 ms, respectively). Conclusions BP elevations following esketamine dosing are generally transient, asymptomatic, and not associated with serious cardiovascular safety sequalae. Further evaluation of long-term cardiovascular outcomes is warranted.

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“…It has the important advantages of not a) increasing intracranial pressure (ICP) (indeed, it may actually decrease ICP in some cases); 49 , 50 b) causing respiratory depression; 51 or c) leading to clinically significant hemodynamic changes. 52 However, its use can be limited by its dissociative effects, which become more pronounced at the higher doses that may be required depending on the degree of agitation. It has a rapid onset of action, and may be an attractive option for cases of severe agitation, especially when the etiology is unknown.…”

Section: Resultsmentioning

confidence: 99%

Current Understanding of the Neurobiology of Agitation

Miller

Hodzic

Weintraub

2020

WestJEM

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Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

Cited by 46 publications

References 25 publications

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program

Current Understanding of the Neurobiology of Agitation

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