Ketamine as a potential new and effective antidepressant
The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established.
There has been growing interest in the observation that ketamine has a rapid positive effect on depressive symptoms. Ketamine is used in medicine for inducing and maintaining anaesthesia, and illicitly for its hallucinogenic and dissociative effects. The fact that ketamine does not work through the ‘conventional’ antidepressant monoaminergic targets of serotonin and noradrenaline has provoked excitement: understanding its effects could provide novel insights into the pathophysiology of depression and open up a new class of medications.
Preclinical studies: biological and molecular pathways
N-methyl-D-aspartate receptor (NMDA-R) antagonists in particular have long been linked to the pathophysiology of MDD ( Major Depressive Disorder) and the mechanism of action of AD (Anti Depressant) drugs. The first pre-clinical work testing the hypothesis that various NMDA-R antagonists have AD-like effects was carried out in mice, where the authors showed that such agents caused a significant reduction of immobility in the FST (Forced Swimming Test) and the tail suspension test, two tests with high predictive validity for AD treatments.
Pre-clinical studies have focused on the mechanisms of action of ketamine. The AD-like effects of ketamine are blocked by pretreatment with 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzol[f]quinoxaline-2,3-dione (NBQX), an a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist.
An early study revealed decreased spontaneous activity of GABAergic interneurons and an increased firing rate of glutamatergic pyramidal neurons in the PFC (Pre Frontal Cortex) of rats given ketamine, suggesting that NMDA-R antagonism by ketamine blocked spontaneous GABAergic activity resulting in enhanced glutamatergic transmission. Stimulation of AMPA receptors leads to activity-dependent BDNF release.
The use of conditional knockout mice has suggested that BDNF is required for the AD-like effect of ketamine. Ketamine also shows an activation of neurotrophin signaling. In particular studies have shown a rather transient increase in the phosphorylation of the BDNF/NT-4 receptor, namely TrkB, following a single sub-anesthetic injection of ketamine in rodents. In a randomized control trial with ketamine, plasma BDNF levels were found to be significantly higher in responders compared to that in non-responders.
Some studies have shown a positive correlation between plasma levels of mTor and its downstream effectors, glycogen synthase kinase-3beta (GSK-3β) and dephosphorylation of eukaryotic elongation factor 2 (e-EF2) in patients who responded to ketamine. Since phosphorylated e-EF2 is associated with inhibition of translation, its dephosphorylation, via mTor signaling activation, leads to increased protein synthesis, including BDNF synthesis.
Clinical evidence
The first randomized controlled trial investigating the AD properties of a single intravenous low dose of ketamine (0.5 mg/kg) in patients diagnosed with MDD showed a significant improvement in depressive symptoms within 72 hours after ketamine administration, and not with placebo. Since this first trial, others have corroborated the rapid AD effects of ketamine administration''. When given to TRD (Treatment Resistant Depression) patients, single subanesthetic dose of ketamine typically improves mood within hours following ketamine administration and can persist, for the most part, for about two weeks''''''.
It also produces a rapid decrease in suicidal ideation in both bipolar depression and MDD. Rapid-acting pharmacotherapy could readily reduce hospitalization time and allow disabled people to resume their daily routine including being able to work.
Safety and collateral effects
It is important to note that aside from the promising and consistent results gained in the clinic, ketamine poses some serious problems with regard to its acute psychotomimetic and physiological (increased blood pressure and heart rate) side effects. In addition, chronic use of ketamine has been associated with dependence''.
Conclusions
The longer-term role of ketamine in the management of depression is unclear. Optimal dosing and longer-term data on relapse prevention and tolerability are lacking. Although most studies administered ketamine at a dose of 0.5 mg/kg in a saline drip over about 40 minutes, this was not the only schedule, with for example a bolus administration of 0.2 mg/kg over 1–2 minutes. Most studies utilized participants with treatment-resistant MDDs: on the one hand this adds to the clinical appeal of a therapy that works on those who have failed to respond to standard treatment; on the other hand it leaves open the question of the effects of ketamine on mild, moderate or treatment-naïve depressive disorders. There is no current consensus whether those who are treatment refractory and fail to respond to traditional antidepressants have a neurobiologically distinct form of the illness.
It currently seems that the primary role of ketamine in depression may turn out to be as a prototype for the development of future glutamatergic antidepressants, and in furthering our understanding of the neuropathology of depression.
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