Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

Shiroma, Paulo; Thuras, Paul; Wels, Joseph; Albott, C. Sophia; Erbes, Christopher R.; Tye, Susannah J.; Lim, Kelvin O.

doi:10.1016/j.jad.2020.08.058

Cited by 31 publications

(27 citation statements)

References 44 publications

(58 reference statements)

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“…Importantly, clinical status moderates the extent to which an individual will experience changes in cognition following ketamine exposure [ 19 ]. Single and repeated ketamine administration exerts pro-cognitive effects in preclinical models of depressive-like behavior [ 98 – 101 ] and in patients with treatment-resistant major depression [ 6 , 21 , 23 , 40 ], especially those suffering from comorbid anxiety [ 40 ]. The cognition-enhancing properties of ketamine observed in patients suffering from depression may be explained by the fact that many of these patients show baseline cognitive deficits [ 24 , 25 ] and may be related at least in part to its antidepressant actions [ 23 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

Riggs

Pereira

et al. 2021

Transl Psychiatry

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A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.

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Section: Discussionmentioning

confidence: 99%

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

Riggs

Pereira

et al. 2021

Transl Psychiatry

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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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“…In one double-blind, randomized, controlled clinical trial of 62 individuals with TRD, ketamine had no deleterious effect on cognitive functioning; in addition, poor processing speed at baseline was associated with improved antidepressant response to ketamine [ 53 ]. In another study of 43 individuals with TRD randomized to receive one or six ketamine infusions, researchers reported some improvements in short-term neurocognitive function, particularly in the domains of processing speed, set shifting, and spatial working memory [ 54 ]. Finally, a recent retrospective study of 68 individuals with TRD found that ketamine had pro-cognitive effects, including depression-independent improvements in working memory as measured by the Trail Making Test [ 55 ].…”

Section: Ketamine For Other Psychiatric Indicationsmentioning

confidence: 99%

Ketamine treatment for depression: a review

et al. 2022

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This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of the novel glutamatergic modulator racemic (R,S)-ketamine (hereafter referred to as ketamine) as well as its S-enantiomer, intranasal esketamine, for the treatment of major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals with MDD and bipolar depression, with antidepressant effects lasting three to seven days. In 2019, esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression (TRD) in adults. Esketamine was approved under a risk evaluation and mitigation strategy (REMS) that requires administration under medical supervision. Both ketamine and esketamine are currently viable treatment options for TRD that offer the possibility of rapid symptom improvement. The manuscript also reviews ketamine’s use in other psychiatric diagnoses—including suicidality, obsessive–compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder—and its potential adverse effects. Despite limited data, side effects for antidepressant-dose ketamine—including dissociative symptoms, hypertension, and confusion/agitation—appear to be tolerable and limited to around the time of treatment. Relatively little is known about ketamine’s longer-term effects, including increased risks of abuse and/or dependence. Attempts to prolong ketamine’s effects with combined therapy or a repeat-dose strategy are also reviewed, as are current guidelines for its clinical use. In addition to presenting a novel and valuable treatment option, studying ketamine also has the potential to transform our understanding of the mechanisms underlying mood disorders and the development of novel therapeutics.

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Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

Cited by 31 publications

References 44 publications

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

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

Ketamine treatment for depression: a review

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