Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment

Ng, Jason; Lui, Leanna M.W.; Rosenblat, Joshua D.; Teopiz, Kayla M.; Lipsitz, Orly; Danielle, S.; Xiong, Jiaqi; Nasri, Flora; Lee, Yena; Kratiuk, Kevin; Rodrigues, Nelson B.; Gill, Hartej; Subramaniapillai, Mehala; Mansur, Rodrigo B.; Ho, Roger; Cao, Bing; McIntyre, Roger S.

doi:10.1007/s00213-021-05767-1

Cited by 20 publications

(7 citation statements)

References 68 publications

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“…From a tolerability and safety perspective, an additional, albeit not treatment-limiting concern with ketamine is the potential for dissociation, as well as vasopressor effects [16][17][18]. Evaluating the long-term effectiveness of ketamine is limited by a dearth of long-term controlled trial data [13,19].…”

Section: Introductionmentioning

confidence: 99%

Strategies to Prolong Ketamine’s Efficacy in Adults with Treatment-Resistant Depression

et al. 2021

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Introduction Ketamine treatment is capable of significant and rapid symptom improvement in adults with treatment-resistant depression (TRD). A limitation of ketamine treatment in TRD is the relatively short duration of time to relapse (e.g., median 2–4 weeks). The objective of the systematic review herein is to identify strategies capable of prolonging the acute efficacy of ketamine in adults with TRD. Methods PubMed/MEDLINE databases were searched from inception to December 2020 for clinical studies written in English using the following key terms: ketamine, prolong, and depression. A total of 454 articles were identified from the literature search which included all clinical studies regarding prolonging the antidepressant effects of ketamine. Twenty-two articles were included: ten randomized controlled trials (RCTs), eight prospective open-label trials, one retrospective chart review, and three case reports. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data extraction. The primary outcome was prolonged effect, defined as statistically significant antidepressant effects following acute ketamine treatment. Results A total of 454 articles were identified, and 22 articles were included. Different treatment modalites including pharmacological interventions, manualized-based psychotherapies, electroconvulsive therapy, transcranial magnetic stimulation, and intravenous monotherapy were examined to determine their impact on the prolongation of antidepressant effects following acute ketamine treatment. No treatment modality, other than repeat-dose IV ketamine, has demonstrated ability to significantly prolong the acute efficacy of IV ketamine in TRD. Conclusion Hitherto, available open-label data and controlled trial data support repeat administration of IV ketamine as an effective strategy to prolong the efficacy of ketamine’s antidepressant effects (although not the focus of the study herein, maintenance repeat-dose esketamine treatment is proven effective in esketamine responders). There is a need to identify multimodality strategies that are safe and capable of prolonging the efficacy of ketamine in adults with TRD.

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Section: Introductionmentioning

confidence: 99%

Strategies to Prolong Ketamine’s Efficacy in Adults with Treatment-Resistant Depression

et al. 2021

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“…In addition, ketamine is an addictive drug, and it is unclear whether its use as a treatment for depression may lead to increased rates of abuse. Bladder toxicity is another potentially worrisome side effect that can result from chronic ketamine exposure [ 63 ]. In the future direction, not only further controlled trials with more flexible doses are needed, but also an in-depth exploration of the mechanism of action of ketamine.…”

Section: Discussionmentioning

confidence: 99%

The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial

et al. 2022

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Background Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. Methods This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. Discussion This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. Trial registration Chinese Clinical Trial Register, ChiCTR2000041232. Registered 22 December 2020.

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“…Besides this, KC patients also experience other side effects such as decreased bladder volume, low bladder compliance, elevated bladder contractive pressure, and overactive bladder condition [8]. The pathogenesis of KC is still elusive; additionally, the risk, severity, and symptoms are related to the drug usage frequency and are dosage-dependent [9]. Several pathological approaches have been postulated, which elucidate the toxic effects of ketamine and its metabolites, such as norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine [8], their interaction with the urothelial cells, and induction of inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

“…It also exhibits signaling properties such as signaling bladder voiding function and managing contractile activity [2]. Ketamine and its metabolites directly rupture the urothelial layer by diminishing the expression of gap junction proteins; hence, the urinary irritant particles rapidly enter via the slackened and conceded bladder wall that ultimately elicits inflammatory responses [9].…”

Section: Introductionmentioning

confidence: 99%

Specific Impacts of Ketamine on Bladder Dysfunction and Associated Histological Alterations in Rats—A Time Course Validation through Transmission Electron Microscopy

Chung

Rajneesh

Chen

et al. 2022

IJMS

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This study explored the specific effects of ketamine on bladder function followed by a sequence of histological changes in a rat bladder at fixed time course intervals. The rats were grouped into normal control and experimental animals, and ketamine (100 mg/kg/day) was administrated to the experimental animals for 2, 4, and 8 weeks, respectively; similarly, the control animals received saline. All animals were evaluated for bladder function and histological responses to the treatment. Ultrastructural changes were observed by transmission electron microscopy (TEM). The results showed progressive bladder dysfunctions with hyperactive bladder conditions according to the time course and frequency of exposure to ketamine. Significantly, decreased inter contraction intervals, residual urine volume, peak micturition pressure, and increased micturition frequency were observed. Bladder histology results revealed substantial inflammation and comprehensive submucosa edema in week 2 and 4 rats along with fibrosis and significant bladder detrusor hypertrophy in week 8 rats. TEM analysis revealed bladder wall thickening, deformed blood vessels, detrusor hypertrophy, wobbled gap junction, and barrier dysfunction at different time course levels in experimental animals. These results provided a profound knowledge about the prognosis and step-by-step pathophysiology of the disease, which might help in developing new therapeutic interventions.

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Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment

Cited by 20 publications

References 68 publications

Strategies to Prolong Ketamine’s Efficacy in Adults with Treatment-Resistant Depression

Strategies to Prolong Ketamine’s Efficacy in Adults with Treatment-Resistant Depression

The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial

Specific Impacts of Ketamine on Bladder Dysfunction and Associated Histological Alterations in Rats—A Time Course Validation through Transmission Electron Microscopy

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