Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

Rawat, Radhika; Tunc-Ozcan, Elif; Dunlop, Sara; Tsai, Yung-Hsu; Li, Fangze; Bertossi, Ryan; Peng, Chian-Yu; Kessler, John A.

doi:10.1007/s00018-024-05121-6

Cited by 3 publications

(2 citation statements)

References 90 publications

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“…A study by Reed et al [ 23 ] used functional magnetic resonance imaging (fMRI) to demonstrate that ketamine administration led to increased activation in the prefrontal cortex, a region associated with emotional regulation and cognitive control [ 23 ]. Another study by Rawat et al [ 24 ] utilized structural MRI to show that ketamine induced rapid and transient increases in hippocampal volume, suggesting a potential role in promoting neurogenesis and synaptic plasticity [ 24 ]. Scheidegger et al [ 25 ] found that ketamine administration reduced amygdala hyperactivity, a common feature of mood disorders, and restored normal fear responses [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Beyond therapeutic potential: a systematic investigation of ketamine misuse in patients with depressive disorders

Juneja,

Afroze,

Goti

et al. 2024

Discov Ment Health

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Ketamine, a pharmacological agent that acts as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, has garnered considerable interest because of its notable and expeditious antidepressant properties observed in individuals diagnosed with major depressive disorder (MDD) who exhibit resistance to conventional therapeutic interventions. A comprehensive and rigorous systematic review was undertaken to evaluate the prevalence of ketamine abuse undergoing ketamine treatment for depressive disorders. A comprehensive search was conducted across the electronic databases to identify pertinent studies published between 2021 and 2023. The present investigation incorporated a comprehensive range of studies encompassing the abuse or misuse of ketamine, including case reports, observational studies, and clinical trials. Data extraction and quality assessment were conducted in accordance with predetermined criteria. The findings of this systematic review demonstrate the importance of monitoring and addressing ketamine abuse in patients receiving ketamine treatment for depressive disorders like MDD. The wide range of reported prevalence rates highlights the need for standardized criteria and measures for defining and assessing ketamine abuse. This study presents a significant contribution to the field by introducing a novel screening questionnaire and assessment algorithm designed to identify and evaluate ketamine misuse among major depressive disorder (MDD) patients undergoing ketamine treatment. This innovative tool holds the potential to enhance clinical practice by providing healthcare professionals with a standardized approach to promptly detect and address ketamine misuse. The integration of this screening tool into routine care protocols can facilitate more effective monitoring and management of ketamine misuse in this population, ultimately leading to improved patient outcomes and safety.

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Section: Discussionmentioning

confidence: 99%

Beyond therapeutic potential: a systematic investigation of ketamine misuse in patients with depressive disorders

Juneja,

Afroze,

Goti

et al. 2024

Discov Ment Health

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“…Intravenous ketamine and intranasal esketamine did not differ in this aspect. Rawat et al discussed the accumulation of the antidepressant effect, suggesting that it was associated with changes in bone morphogenetic protein signaling (Rawat et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

Ketamine in severe, highly treatment-resistant depression—a retrospective case study and a perspective

Turkia

2024

Preprint

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Ketamine is a well-known and widely available general anesthetic from the 1960s that, in sub-anesthetic doses, has been adopted in a limited manner for the treatment of acute suicidality and treatment-resistant depression. Its short onset time and short duration of action make it feasible for use at outpatient clinics. In the US, it has a long history of off-label use and was officially approved for depression treatment in 2019. In Finland, it has been administered to selected hospitalized patients in the public healthcare system since 2010 and became available at a private outpatient clinic very recently. In Norway, it has been administered off-label at a private clinic for approximately 500 patients since mid-2010s and at a public clinic for approximately 300 patients since 2020, with plans on opening more clinics in 2024. In the US, the treatment has been administered to hundreds of thousands of patients. The retrospective ethnographic inquiry part of this study features a Finnish woman in her twenties who suffered from treatment-resistant depression, rooted in her insecure childhood and having been bullied at school, as well as income insecurity and excessive workload in adulthood. Eventually, she was violently raped, which induced an obvious post-traumatic stress disorder and exacerbated her depression, incapacitating her. In the course of approximately five years, she was prescribed ten different anti-depressive medications and seventeen other medications, including various antipsychotic medications and lithium. These failed to provide an anti-depressive effect but resulted in 'massive' adverse effects instead, including 60% weight gain and psychotic hallucinations. Eventually, esketamine spray treatment at a private outpatient clinic resolved her depression in a single session. A weekly re-administration process was ongoing. In this case, repeated esketamine administration alleviated depression by producing accumulating corrective emotional experiences without the need to re-experience previous traumatizing events. In a few months to a year, the transient but accumulating anti-depressive effect typically leads to the resolution of depression in most cases, if the patients' living conditions no longer constantly re-traumatize them. It is necessary to adopt ketamine more widely as an emergency measure while more effective, non-addictive alternatives and complements are prepared for adoption. The cost of this specific pilot program implementation was unscalable, but costs can be reduced by approximately 90% by modifying the implementation details. Ketamine and its more effective alternative, 5-MeO-DMT, can serve a major role in facilitating a rebirth of public and private mental healthcare systems, with treatment efficacy multiplied and treatment costs simultaneously reduced.

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Fast-acting antidepressant-like effects of ketamine in aged male rats

Hernández-Hernández,

Ledesma-Corvi,

Jornet-Plaza

et al. 2024

Pharmacol. Rep

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Background The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine’s effects in older rats. Methods The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation. Results Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine. Conclusions These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.

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Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

Cited by 3 publications

References 90 publications

Beyond therapeutic potential: a systematic investigation of ketamine misuse in patients with depressive disorders

Beyond therapeutic potential: a systematic investigation of ketamine misuse in patients with depressive disorders

Ketamine in severe, highly treatment-resistant depression—a retrospective case study and a perspective

Fast-acting antidepressant-like effects of ketamine in aged male rats

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