Working memory associated with anti-suicidal ideation effect of repeated-dose intravenous ketamine in depressed patients

Chen, Xiaoyu; Wang, Mingqia; Hu, Yiru; Zhan, Yongle; Zhou, Yanling; Zheng, Wei; Liu, Weijian; Wang, Chengyu; Zhong, Xiaomei; Li, Hanqiu; Lan, Xiaofeng; Ning, Yuping; Zhang, Bin

doi:10.1007/s00406-020-01221-z

Cited by 18 publications

(14 citation statements)

References 43 publications

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“…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 ]. Thus, it is noteworthy that ( R,S )-ketamine has beneficial effects on cognitive impairment in depressed patients.…”

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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Section: Introductionmentioning

confidence: 99%

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

2021

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“…An open-label clinical trial of 25 patients with TRD who received a single 0.5 mg/kg ketamine infusion demonstrated the correlation between greater deficits in processing speed (p = 0.008) and working memory (p = 0.045) at baseline with a stronger antidepressant response to ketamine infusion [14]. Chen et al highlighted the relationship between working memory and antidepressant effect in patients with TRD receiving repeated ketamine treatments and found a negative association between improvement in depressive symptoms and pretreatment working memory (p = 0.042) [19]. Consistent with previous results, the current study validated the negative relationship between working memory at baseline and the antidepressant effect of low-dose ketamine infusion.…”

Section: Discussionmentioning

confidence: 99%

Baseline Working Memory Predicted Response to Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression

Chen

Lin

et al. 2021

Pharmacopsychiatry

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Introduction Pretreatment neurocognitive function may predict the treatment response to low-dose ketamine infusion in patients with treatment-resistant depression (TRD). However, the association between working memory function at baseline and the antidepressant efficacy of ketamine infusion remains unclear. Methods A total of 71 patients with TRD were randomized to one of three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HDRS) at baseline and after treatment. Cognitive function was evaluated using working memory and go-no-go tasks at baseline. Results A generalized linear model with adjustments for demographic characteristics, treatment groups, and total HDRS scores at baseline revealed only a significant effect of working memory function (correct responses and omissions) on the changes in depressive symptoms measured by HDRS at baseline (F=12.862, p<0.05). Correlation analysis further showed a negative relationship (r=0.519, p=0.027) between pretreatment working memory function and changes in HDRS scores in the 0.5 mg/kg ketamine group. Discussion An inverse relationship between pretreatment working memory function and treatment response to ketamine infusion may confirm that low-dose ketamine infusion is beneficial and should be reserved for patients with TRD.

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“…This study was part of a longitudinal and open‐label trial using ketamine for depression, conducted at the Affiliated Brain Hospital of Guangzhou Medical University (Chen et al, 2021; Y. L. Zhou et al, 2020; Zheng et al, 2020). This clinical trial was approved by the Clinical Research Ethics Committees of the Affiliated Brain Hospital of Guangzhou Medical University and was registered at http://www.chictr.org.cn/ (registration number: ChicCTR‐OOC‐17012239).…”

Section: Methodsmentioning

confidence: 99%

Functional connectivity between the habenula and default mode network and its association with the antidepressant effect of ketamine

Wang

Chen

et al. 2021

Depression and Anxiety

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Background: Recently, an animal model for depression has shown that ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, elicits a rapid-acting antidepressant effect by blocking NMDAR-dependent bursting in the lateral habenula (Hb). However, evidence from human studies remains scarce.Methods: This study explored the changes of resting-state functional connectivity (FC) of the Hb in responders and nonresponders who was diagnosed with unipolar or bipolar depression before and after ketamine treatment. The response was defined as a ≥50% reduction in the total MADRS score at Day 13 (24 h following the sixth infusion) in comparison with the baseline score. Correlation analyses were performed to identify an association between symptom improvement and the signals of the significantly different brain regions detected in the above imaging analysis.Results: In the post-hoc region-of-interest analysis, an enhanced baseline FC between Hb and several hubs of the default mode network (including angulate cortex, precuneus, medial prefrontal cortex, and middle temporal cortex) was observed in responders (≥50% decrease in the Montgomery-Asberg Scale at 2 weeks) compared with nonresponders.Conclusions: These pilot findings may suggest a potential neural mechanism by which ketamine exerts its robust antidepressant efficacy via downregulation of aberrant habenular FC with parts of the default mode network.

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Working memory associated with anti-suicidal ideation effect of repeated-dose intravenous ketamine in depressed patients

Cited by 18 publications

References 43 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

Baseline Working Memory Predicted Response to Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression

Functional connectivity between the habenula and default mode network and its association with the antidepressant effect of ketamine

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