Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy

Abstract

The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.

Keywords: antidepressant; glutamatergic; ketamine.

Figure 1.

Schematic illustration of the effects of ketamine. (A) Normal and pathological physiology: the prefrontal cortex (PFC) homeostatically limits input via a feedback loop to GABAergic interneurons. The mesolimbic pathway can increase such input through dopaminergic modulation from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc). There is evidence for dysregulation of PFC connectivity patterns in depression, particularly between the default mode network (DMN) and the extrinsic network (Ex network). In schizophrenia there is evidence for both underactive PFC glutamatergic feedback to GABA interneurons and overactive dopaminergic activity in the mesolimbic system, both of which serve to pathologically dysregulate PFC activity. (B) The effects of ketamine: ketamine is an antagonist at the glutamatergic NMDA receptor, but not the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, increasing the relative activation at the latter. Effects of ketamine binding are dose dependent. At lower doses it appears to alter PFC connectivity from a ‘depressive pattern’ of excess DMN activation to a more ‘normal’ pattern. Ketamine can be psychotomimetic: its antagonism at GABA interneurons reduces thalamic inhibition mimicking psychotic pathology without involving the dopaminergic system. (C) Through relative increase in activation, intracellular changes from AMPA receptors are affected. Evidence for several types of change have been discovered, including altering intracellular signalling pathways, binding with endoplasmic reticulum (ER) sigma-one (σ₁) receptors, and changing production of cellular proteins such as mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF).

Figure 2.

Flow diagram demonstrating the process of inclusion of studies for review.

Figure 3.

Forest plots for the efficacy of ketamine compared with placebo at baseline (top), 60–80 minutes (middle) and 210–230 minutes (bottom).