Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series

Lipsitz, Orly; Vincenzo, Joshua D. Di; Rodrigues, Nelson B.; Danielle, S.; Lee, Yena; Greenberg, David M.; Teopiz, Kayla M.; Ho, Roger; Cao, Bing; Lin, Kangguang; Subramaniapillai, Mehala; Flint, Alastair J.; Kratiuk, Kevin; McIntyre, Roger S.; Rosenblat, Joshua D.

doi:10.1016/j.jagp.2020.12.032

Cited by 29 publications

(14 citation statements)

References 52 publications

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“…In addition, the authors did not take into account the timing of the menstrual cycle and the use of contraceptives, which may be vital when assessing the influence of gonadal hormones on the response to ketamine 59 . Thus, the use of ketamine and esketamine in perimenopausal women with TRD and MDD may warrant further investigation 58,60 . Although the use of ketamine in pregnancy has not been approved due to developmental neurotoxicity, 1 study suggests the use of E2 to prevent ketamine‐induced neurotoxicity in pregnancy 61 …”

Section: Potential Determinants Of Variability In the Pharmacodynamic...mentioning

confidence: 99%

“…59 Thus, the use of ketamine and esketamine in perimenopausal women with TRD and MDD may warrant further investigation. 58,60 Although the use of ketamine in pregnancy has not been approved due to developmental neurotoxicity, 1 study suggests the use of E2 to prevent ketamine-induced neurotoxicity in pregnancy. 61…”

Section: Potential Determinants Of Variability In the Pharmacodynamic...mentioning

confidence: 99%

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Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Langmia

Just

Yamoune

et al. 2022

Brit J Clinical Pharma

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Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

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Section: Potential Determinants Of Variability In the Pharmacodynamic...mentioning

confidence: 99%

Section: Potential Determinants Of Variability In the Pharmacodynamic...mentioning

confidence: 99%

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Langmia

Just

Yamoune

et al. 2022

Brit J Clinical Pharma

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“…Compared to conventional antidepressants, IV ketamine is differentiated by (1) efficacy in patients with TRD, (2) a relatively rapid onset of therapeutic effect, and (3) preliminary evidence for reducing suicidality [10,15]. 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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“…Few studies examine outcomes of the N-methyl- d -aspartate (NMDA) receptor channel inhibitors ketamine and esketamine in LLD. Both a small, randomized trial of subcutaneously administered ketamine and larger open-label study of intravenous ketamine improved depression severity in older adults with treatment-resistant depression [ 244 , 245 ]. Intravenous ketamine resulted in a remission rate of 12.8% for older individuals, which is comparable to remission rates seen in patients progressing to later stages of the STAR*D study [ 245 , 246 ].…”

Section: Updates On Established Somatic Treatmentsmentioning

confidence: 99%

Biological factors influencing depression in later life: role of aging processes and treatment implications

Szymkowicz,

Gerlach,

Homiack

et al. 2023

Transl Psychiatry

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Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits, reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms. Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to dysfunctional states and increasing allostatic load through the hypothalamic–pituitary–adrenal axis and inflammatory processes. Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus, while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and maintenance of remission.

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Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series

Cited by 29 publications

References 52 publications

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

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

Biological factors influencing depression in later life: role of aging processes and treatment implications

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