The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression: A randomized controlled study

Li, Cheng Ta; Chen, Mu Hong; Lin, Wei Chen; Chen, Hong; Yang, Bohan; Liu, Ru‐Shi; Tu, Pei Chi; Su, Tung Ping

doi:10.1002/hbm.23085

Cited by 117 publications

(85 citation statements)

References 45 publications

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“…Many reports have showed that CSDS induces molecular and circuit abnormalities including alterations in BDNF-TrkB signaling, ΔFosB signaling, and prefrontal cortexamygdala circuitry [63,65,72], consistent with studies of MDD patients [73][74][75][76]. Importantly, CSDS mice also respond to the rapid-acting antidepressant ketamine [47,77,78], which is known to be efficacious even in treatment-resistant patients and to depend on alterations in glutamate homeostasis [79][80][81]. Thus, while CSDS mice are not exclusively a model of treatmentresistant depression, they do exhibit predictive validity for one of the few pharmacotherapies effective at treating refractory depression through a mechanism distinct from monoaminergic agents.…”

Section: Discussionsupporting

confidence: 60%

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

Zhu

Nedelcovych

Thomas

et al. 2018

Neuropsychopharmacol

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There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.

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Section: Discussionsupporting

confidence: 60%

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

Zhu

Nedelcovych

Thomas

et al. 2018

Neuropsychopharmacol

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“…In healthy subjects, functional connectivity between the rACC and mPFC increased acutely (95) and decreased 24 hours after ketamine infusion (96). Furthermore, using PET imaging methods, ketamine associated with increased glucose metabolism in the dorsal ACC (dACC) (97), altered glucose metabolism in PFC regions (97–99) in MDD, and increased glucose metabolism in the dACC and putamen in BD patients (100). Our group has shown that sgACC hypermetabolism predicted response to ketamine in BD patients (101).…”

Section: Ketamine and Functional Neural Circuitry In Depressionmentioning

confidence: 99%

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Lener

Niciu

Ballard

et al. 2017

Biological Psychiatry

373

214

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In patients with major depressive disorder (MDD) or bipolar disorder (BD), abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic dose ketamine has led to a collection of studies that have examined neurochemical (e.g. glutamatergic and GABA-ergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.

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“…Cortical Excitation. Though competing explanations for the rapid antidepressant effects of ketamine have been proposed, most converge on the idea that subanesthetic (i.e., antidepressant) doses of ketamine lead to widespread cortical excitation and increases in energy metabolism (Breier et al, 1997;Lu et al, 2008;Li et al, 2016a;Abdallah et al, 2018a) (Fig. 2).…”

Section: Examining Rapid Antidepressant Effects Through Encodingmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

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Brain and Mind Doctoral Program (S.K.), the Orion Research Foundation (S.K.), and the Emil Aaltonen foundation (S.K.). T.R. and S.K. are listed as coinventors on a patent application, wherein new tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed based on the basic principles of ENCORE-D. T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki.

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The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression: A randomized controlled study

Abstract: Ketamine's rapid antidepressant effects involved the facilitation of glutamatergic neurotransmission in the PFC.

Cited by 117 publications

References 45 publications

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

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