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

Abstract

SUMMARYWhat is known and objective: The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. Comment: Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose-response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. What is new and conclusion: It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders. WHAT IS KNOWN AND OBJECTIVERecent evidence strongly suggests that ketamine produces a rapidonset antidepressant effect in humans with major depressive disorder (MDD). [1][2][3] This commentary focuses on the evidence for the efficacy of ketamine as a rapid-onset antidepressant and the implications of its mechanism of action for yielding insight into the biochemical basis of MDD.MDD is a serious neuropsychological disorder associated with significant morbidity and mortality (suicide). The reported lifetime prevalence of MDD varies widely by country (generally within the range 8-12%). 4 Estimates for the United States are higher, closer to 17%. Worldwide, approximately 300 million people are affected. 5 A diagnosis of MDD is about twice as common in women (8-10%) as in men (3-5%), 6,7 but it is not certain whether this represents a physiological difference or a reporting difference. 8 A first depressive episode is most likely to occur between the ages of 30 and 40 years 9 , and the aetiology is multifactorial, involving biological and psychosocial contributions. Some evidence links it to short alleles of the 5-HT (5-hydroxytryptamine, serotonin) transporter gene SLC6A4 10 located on human chromosome 17 (17q11Á1-q12). 11 The three modalities most commonly used currently for the management of MDD are psychotherapy, pharmacotherapy and ECT (electroconvulsive therapy). Combinations of them are also used effectively. 12 But none provide complete efficacy in all patients. Among the most studied forms of psychotherapy for depression are cognitive behavioural therapy (CBT) 13 and variations of this approach. 14 Studies report good results of CBT for certain patients and symptoms, 15 and it appears to be beneficial in preventing relapse when used as part of a comprehensive treatment plan. 16 A significant drawback is that the suicide attempt rate remains higher than baseline for weeks or even months after initiation of therapy. 17 The efficacy of antidepressant pharmacotherapy 18,19 has been reported to be somewhat superior to that of psychother...

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

“…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.…”

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

“…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.…”

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

“…[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.…”

“…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.…”