Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers

Passie, Torsten; Adams, Hans Anton; Logemann, Frank; Brandt, Simon D.; Wiese, Birgitt; Karst, Matthias

doi:10.1016/j.euroneuro.2021.01.005

Cited by 20 publications

(24 citation statements)

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“…In addition to positive and negative symptoms, intravenous administration of ( R,S )-ketamine (0.5 mg/kg) was reported to produce cognitive impairments in healthy control subjects [ 166 ]. A recent randomized, double-blind, placebo-controlled study in young healthy subjects demonstrated that intravenous administration of esketamine (0.1 mg/kg/min for 5 min and 0.006 mg/kg/min for 60 min) and ( R,S )-ketamine (0.2 mg/kg/min for 5 min and 0.012 mg/kg/min for 60 min) produced significant psychopathological and neurocognitive impairment compared to the placebo [ 167 ]. Interestingly, esketamine, but not ( R,S )-ketamine, significantly increased the auditory alterations subscore of the five-dimensional questionnaire for the assessment of altered states of consciousness; this finding suggests that arketamine exerts a potential protective effect against esketamine-induced psychotomimetic effects [ 167 ].…”

Section: Introductionmentioning

confidence: 99%

“…Surprisingly, six infusions of ( R,S )-ketamine (0.5 mg/kg) significantly ameliorated cognitive impairment, as measured by processing speed, in patients with treatment-resistant MDD or BD [ 168 – 170 ]. A recent systematic review revealed that ( R,S )-ketamine infusion showed significant improvements in cognitive impairment in patients with treatment-resistant MDD, although ( R,S )-ketamine did not worsen cognitive function in depressed patients [ 171 ], as had been observed in healthy controls [ 166 , 167 ]. Furthermore, it was suggested that the improvement in working memory may be predictive of the anti-suicidal-ideation response to ( R,S )-ketamine in patients with treatment-resistant MDD [ 172 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

2021

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The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson’s disease, osteoporosis, inflammatory bowel diseases, and stroke.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

2021

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“…Interestingly, Leal et al (2020), in a pilot study in TRD patients observed that (R)ketamine (arketamine) might produce a fast (60 min) and sustained antidepressant effect (7 days). On the other hand, Passie et al (2021) in an interesting placebo-controlled study in healthy volunteers (n = 10), found no significant difference between the neuropsychological and psychopathological effects of two equivalent doses of (R,S)-ketamine and (S)-ketamine. Therefore, on the basis of this consideration it is likely that the choice of the right ketamine's enantiomer for the treatment of TRD or other forms of depression will be further debated (Hashimoto, 2019).…”

Section: Esketamine: Clinical Use In Depressionmentioning

confidence: 92%

“…On this basis, we can speculate that the rapid response of ketamine in responsive patients suggests that it is capable of activating brain circuits that may be only temporarily deactivated, and that this type of response may not be observed when ketamine is taken by healthy volunteers; reversibly circuits that are activated in the latter may not be available in MDD or TRD individuals. Interestingly, different enantiomers of ketamine might produce different effects and these effects might interact when (R,S)ketamine is administered as reported by Passie et al (2021) who suggested that (S)-ketamine and (R,S)-ketamine differ somewhat regarding their psychopathological effects. This observation may be relevant when evaluating the effects of ketamine in patients with TRD.…”

Section: Subgenual Cingulate Regionmentioning

confidence: 96%

“…In general, and probably because of the extent of glutamate transmission in the brain, it can be suggested that the response to ketamine is closely related to the emotional state of the individual and therefore both rapid and prolonged effects can be very different between individuals; in this regard, Aust et al (2019) with an interesting study, have shown that the state of anxiety induced by ketamine in depressed patients is predictive (inversely proportional) of the antidepressant response of ketamine. In addition, the different individual response could still be different following the administration of (R-S)-, (S)-, or (R)-ketamine administration (Passie et al, 2021). In contrast with the two most used drugs for preventing suicidal behavior (i.e., clozapine and lithium), which require weeks for producing their beneficial effect, ketamine can reduce suicidal ideation rapidly (Vermeulen et al, 2019).…”

Section: Ketamine and Suicidal Behaviormentioning

confidence: 99%

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Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

et al. 2021

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Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine’s use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

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Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain

et al. 2023

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ImportanceRepeated ketamine administration is common in treatment-refractory chronic pain, but ketamine analgesic and antidepressant effects are poorly understood in patients with chronic pain with depression symptoms.ObjectiveTo determine clinical pain trajectories with repeated ketamine administrations, exploring whether ketamine dose and/or pretreatment depressive and/or anxiety symptoms may mediate pain relief.Design, Setting, and ParticipantsThis nationwide, multicenter, prospective cohort study included patients in France with treatment-refractory chronic pain who received repeated ketamine administration, over 1 year, according to ketamine use in their pain clinic. Data were collected from July 7, 2016, through September 21, 2017. Linear mixed models for repeated data, trajectory analysis, and mediation analysis were performed from November 15 to December 31, 2022.InterventionsKetamine administration in cumulative dose (milligrams) over 1 year.Main Outcomes and MeasuresPrimary outcome was mean pain intensity (0-10 on the Numerical Pain Rating Scale [NPRS]), assessed every month for 1 year by telephone, after inclusion in the hospital. Depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), quality of life (12-item Short Form Health Survey [SF-12]), cumulative ketamine dose, adverse effects, and concomitant treatments were secondary outcomes.ResultsA total of 329 patients (mean [SD] age, 51.4 [11.0] years; 249 women [75.7%] and 80 men [24.3%]) were enrolled. Repeated ketamine administration was associated with a decrease of NPRS (effect size = −0.52 [95% CI, −0.62 to −0.41]; P &lt; .001) and an increase of SF-12 mental health (39.7 [10.9] to 42.2 [11.1]; P &lt; .001) and physical health (28.5 [7.9] to 29.5 [9.2]; P = .02) dimension scores over 1 year. Adverse effects were in the normal range. There was a significant difference between patients without and with depressive symptoms in pain diminution (regression coefficient, −0.04 [95% CI, −0.06 to −0.01]; omnibus P = .002 for interaction of time × baseline depression [HADS score ≤7 or &gt;7]). The mediation model showed that ketamine dose was not associated with pain diminution (r = 0.01; P = .61) and not correlated with depression (r = −0.06; P = .32), and that depression was associated with pain diminution (regression coefficient, 0.03 [95% CI, 0.01-0.04]; P &lt; .001), whereas ketamine dose was not (regression coefficient, 0.00 [95% CI, −0.01 to 0.01]; P = .67). The proportion of reduction of pain mediated by baseline depression was 64.6%.Conclusions and RelevanceThe findings of this cohort study on chronic refractory pain suggest that depression (and not ketamine dose or anxiety) was the mediator of the association of ketamine with pain diminution. This finding provides radically new insights on how ketamine reduces pain primarily by dampening depression. This reinforces the need for systematic holistic assessment of patients with chronic pain to diagnose severe depressive symptoms where ketamine would be a very valuable therapeutic option.

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Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers

Cited by 20 publications

References 65 publications

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain

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