Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression

Drewniany, E.; Han, Ji Youn; Hancock, Counce; Jones, Rebecca; Lim, Jinhwan; Gorgani, N. Nemat; Sperry, J. K.; Yu, Hua; Raffa, Robert B.

doi:10.1111/jcpt.12238

Cited by 26 publications

(22 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In people with schizophrenia, in contrast, quinolinic acid production is less efficient due to the dysfunction of KMO, diverting kynurenine pathway metabolism towards enhanced kynurenic acid formation (Holtze et al 2012; Wonodi et al 2011, 2014). Of note, this scenario would not only be in line with the efficacy of NMDA antagonists as rapidly acting antidepressants (Coyle and Laws, 2015; Drewniany et al, 2015; Machado-Vieira et al, 2009) but raises the possibility that interventions causing an elevation of brain kynurenic acid levels may provide clinical benefits in major depressive disorders.…”

Section: Future Directionsmentioning

confidence: 94%

The kynurenine pathway and the brain: Challenges, controversies and promises

2017

View full text Add to dashboard Cite

Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter.

show abstract

Section: Future Directionsmentioning

confidence: 94%

The kynurenine pathway and the brain: Challenges, controversies and promises

2017

View full text Add to dashboard Cite

show abstract

“…Preclinical studies on the mechanisms underlying the antidepressant effect of NMDAR antagonists such as ketamine suggest that the glutamate system is a key target for developing novel antidepressant drugs with fast onset of action and broader efficacy (Covvey et al, 2012; Murrough, 2012; Hasselmann, 2014). Recently, a growing number of clinical studies indicate that ketamine improves depressive symptoms quickly, within hours (Salvadore et al, 2009; Larkin and Beautrais, 2011; Ghasemi et al, 2014; Drewniany et al, 2015). Notwithstanding, a growing number of studies also point to many different mechanisms of action of ketamine, but it is still not completely clear.…”

Section: Introductionmentioning

confidence: 99%

S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression

Ardalan

Wegener

Rafati

et al. 2016

IJNPPY

View full text Add to dashboard Cite

Background:The neurovascular plasticity of hippocampus is an important theory underlying major depression. Ketamine as a novel glutamatergic antidepressant drug can induce a rapid antidepressant effect within hours. In a mechanistic proof of this concept, we examined whether ketamine leads to an increase in synaptogenesis and vascularization within 24 hours after a single injection in a genetic rat model of depression.Methods:Flinders Sensitive Line and Flinders Resistant Line rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline. One day later, their behavior was evaluated by a modified forced swim test. Microvessel length was evaluated with global spatial sampling and optical microscopy, whereas the number of asymmetric synapses was quantified through serial section electron microscopy by using physical disector method in the CA1.stratum radiatum area of hippocampus.Results:The immobility time in the forced swim test among Flinders Sensitive Line rats with ketamine treatment was significantly lower compared with Flinders Sensitive Line rats without treatment. The number of nonperforated and perforated synapses was significantly higher in the Flinders Sensitive Line-ketamine vs the Flinders Sensitive Line-vehicle group; however, ketamine did not induce a significant increase in the number of shaft synapses. Additionally, total length of microvessels was significantly increased 1 day after ketamine treatment in Flinders Sensitive Line rats in the hippocampal subregions, including the CA1.stratum radiatum.Conclusion:Our findings indicate that hippocampal vascularization and synaptogenesis is co-regulated rapidly after ketamine, and microvascular elongation may be a supportive factor for synaptic plasticity and neuronal activity. These findings go hand-in-hand with the behavioral observations, where ketamine acts as a potent antidepressant.

show abstract

“…[18][19][20][21][22] The onset of effects can be as short as a few hours or days after a single administration, and the effect persists for days or a week, long enough for other antidepressant therapy to begin to become effective. 6 Unfortunately, ketamine suffers from adverse effects and abuse potential. 23 Thus, there is impetus for the discovery of other substances with the same on-target (antidepressant) effect, but with less off-target effects.…”

Section: Commentarymentioning

confidence: 99%

“…A body of evidence strongly implicates inhibition of the NMDA receptor as the mechanism of ketamine's antidepressant action. 6 However, the competing view that was recently proposed by Zanos Although there is strong evidence for the prevailing theories that implicate NMDA or AMPA receptors, ketamine binds promiscuously to other receptor types, and therefore, it has rather complex pharmacology. One or more of these other mechanisms might be responsible, or contributory, to the antidepressant effect.…”

Section: Commentarymentioning

confidence: 99%

The rapid‐onset antidepressant effect of ketamine: More surprises?

2017

Self Cite

View full text Add to dashboard Cite

SummaryWhat is known and objective: An effective rapid-onset treatment for major depressive disorder could save lives. Extensive preclinical and clinical data demonstrate such an action of ketamine. However, the presumptive mechanism of action, inhibition of NMDA (N-methyl-D-aspartate) receptors, has recently been challenged. Elucidation of the mechanism is important clinically for drug discovery and for understanding the (patho)physiology of depression. Comment:The best-known pharmacologic property of ketamine is non-competitive inhibition of the NMDA subtype of glutamate receptor. Although other mechanisms have been postulated, this action has been assumed the major one that accounts for ketamine's antidepressant effect. However, a ketamine metabolite and a different mechanism have now been claimed to be necessary and sufficient for the effect. What is new and conclusion:A metabolite has been proposed to be responsible for the antidepressant action of ketamine, via activation of non-NMDA receptors. It will be important to determine which of the competing views is correct. K E Y W O R D SAMPA receptor, antidepressant, ketamine, metabolite, NMDA receptor | WHAT IS KNOWN AND OBJECTIVECurrent therapy for treatment of depressive disorders, whether pharmacologic or non-pharmacologic, often requires weeks of treatment before clinically significant improvement is noted.1 The lag time between initiation of therapy and the onset of clinical effectiveness is serious, because depressed patients are at increased risk of suicide, 2 and perhaps at increased risk during the lag time. 3,4 In addition, the delay raises questions about the apparent disconnect between the clinical effect and the molecular mechanism of antidepressant drugs. For example, inhibition of the neuronal reuptake of serotonin or noradrenaline occurs quickly; 5 thus, there is disconnect between the molecular events, which occur rapidly, and the clinical effect, which is delayed.The extensive preclinical and clinical evidence that convincingly demonstrates a rapid-onset antidepressant action of ketamine was previously reviewed. 6 The findings are both exciting and surprising.They are exciting because the reduction in delay between therapy initiation and clinical benefit is potentially life-saving; and they are surprising because no other therapeutic intervention works so rapidly, and because ketamine is most widely known as being an analgesic agent, 7 not as an antidepressant. Unfortunately, there are undesirable aspects of ketamine that will likely limit its widespread use for this purpose, namely dysphoric effects and abuse potential. 8 In order that more clinically amenable compounds can be discovered or developed, it is important to understand the mechanism(s) by which ketamine produces its rapid antidepressant effect. | COMMENTARYA recent report by Zanos et al published in Nature 9 proposes that (i) a metabolite of ketamine, actually one enantiomer of the metabolite, is

show abstract

Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression

Cited by 26 publications

References 76 publications

The kynurenine pathway and the brain: Challenges, controversies and promises

The kynurenine pathway and the brain: Challenges, controversies and promises

S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression

The rapid‐onset antidepressant effect of ketamine: More surprises?

Contact Info

Product

Resources

About