The authors have declared that no competing interests exist.
Ketamine’s potential as a fast-acting reagent to treat MDD, especially treatment-resistant depression has caught much attention recently. Although much has been learned about the biological mechanisms underlying ketamine’s effect, there are a few critical issues remained to be resolved. This mini review will briefly discuss several controversial issues that warrant further studies, regarding the molecular, physiological, psychopharmacological, and behavioral effects of ketamine. Understand how ketamine works as an anti-depressant will open the door to better understanding of MDD and its treatment.
Despite current available antidepressants, major depressive disorder (MDD) presents as a major threat to public health, with a lifetime prevalence of 17% in the United States and 40-50% of patients unresponsive to treatment
Ketamine is a low-affinity, activity-dependent, open channel blocker of NMDA subtype glutamate receptors (NMDARs). Ketamine has been shown to be effective in treating major depressive disorder (MDD), including treatment-resistant depression, with a rapid onset (on the order of hours) of efficacy and effective duration of days to weeks
After the serendipitous discovery of its antidepressant effects, ketamine has been successfully applied as a fast acting treatment of MDD in a clinical setting, especially for treatment-resistant MDD patients
A few biological mechanisms have been proposed for ketamine’s anti-depressant effect: (1) blockade of NMDARs on the GABAergic inhibitory neurons leads to reduced activation and enhanced excitation in the brain, the so called disinhibition hypothesis
Although ketamine has shown huge potentials to be a major breakthrough in treating MDD, especially treatment-resistant depression, there are a few critical unresolved issues. A better understanding of these issues will not only facilitate ketamine’s approval for clinical use, but also provide important biological insights into the pathogenesis of MDD and its more effective treatment.
Is there anything special for ketamine as NMDAR antagonist In addition to ketamine, various NMDAR antagonists have been tested for their anti-depression efficacy, all with inferior efficacy than ketamine but some with better side-effect profiles
Addictive potential: As one of the popular recreational drugs, Ketamine’s psychostimulant effects are also deemed to induce addictive behaviors
Dissociative thoughts: Originally used as an anesthetic and analgesic drug due to it dissociative effects and distinct from other canonical anesthetic drugs, ketamine induces psychotropic effects ranging from dissociation to schizophrenia-like symptoms (positive, negative, and cognitive deficits)
Can AMPAR potentiators be an alternative and perhaps a better option? A recent study by Zanos and colleagues demonstrated that one of the main metabolites of ketamine, 6-hydroxy norketamine ((2R,6R)-HNK ), is the main mediator of ketamine’s anti-depressant effect
Is synaptic plasticity required? The fact that repetitive infusion of ketamine is required to prevent relapse of depressive symptoms suggests that no lasting changes have occurred with ketamine administration and hence unlikely plasticity is required for its efficacy. Furthermore, although preclinical studies have shown increased density of dendritic spines and increased number of AMPARs9-10, no study has demonstrated a clear increase of synaptic connections in an input-specific manner. If new connections are formed, where do the presynaptic inputs come from? Are they branching off the existing ones or converting silent synapse into functioning ones? A possible mechanism is that ketamine induces metaplasticity to alter the subsequent generation of plasticity. Preliminary report showed ketamine may exert antidepressant effects via modulation of metaplasticity
What major brain regions are involved? Two likely regions are hippocampus and PFC, and it will be quite informative to compare ketamine and its metabolite, or other NMDAR antagonists, or AMPAR potentiators, to understand whether they activate distinction brain regions.
Ketamine offers a golden opportunity, to both serve as an anti-depressant drug and to our better understanding of the pathology of MDD. One of the critical questions is whether NMDAR antagonism is required for ketamine’s fast action. Once we are sure of this, the path forward is straighter.
This work is supported by Shenzhen Municipal Science and Technology Innovation Council
Grant No:JCYJ20150529153646078, ZDSYS201504301539161,JSGG20140703163838793.