How much of ketamine's antidepressant response is shared with ethanol?

In the informative review by Schoevers et al ¹ about ketamine's potency in the management of pain and treatment-resistant depression, the authors perceive a latent risk of ketamine misuse resulting from these treatments and forecast that misuse will become more prominent if ketamine is used broadly in clinical practice. At this juncture, it should be emphasised that acute ethanol shares some pharmacological features with ketamine, all being parts of a cascade that precipitates enhanced synaptogenesis and connectivity in cortico-limbic networks: ² non-competitive antagonism of glutamatergic N-methyl-D-aspartate (NMDA) receptors; disinhibition of pyramidal cells producing an extracellular glutamate surge; amplification of glutamate non-NMDA receptor and downstream mammalian target of rapamycin (mTOR) signalling pathways; and increase in neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)). ³ All of these are assumed to contribute to the generation of ketamine's rapid but short-term antidepressant response. ²

When ethanol vapour is repeatedly applied to rodents, their prefrontal pyramidal neurons develop an increase in dendritic spine density in the first abstinence days, ⁴ which may resemble the synaptic remodelling observed after a single sub-anaesthetic ketamine pulse. ² While the first is interpreted as reflecting plasticity changes on the way to addiction, ⁴ the second has been shown to reverse chronic-stress-mediated decreases in spine density and is assumed to morphologically represent the antidepressant response. ² Do a few ethanol pulses work similarly, ‘refreshing’ on stressed spines of a non-addicted brain? Intriguingly, low ethanol doses are followed by antidepressant-like effects in Porsolt's swim test on mice. ³

Against this background, there remain in my mind a few primarily depressed alcohol-dependent individuals, who reported an improvement of their depressed state after a few glasses of beer or wine. This improvement lasted for some abstinent days (ethanol's antidepressant response); however, this was only in the beginning of their drinking career. To cope with depression more sustainably, these patients gradually increased the frequency and amount of alcohol intake, which resulted in hangover and tolerance to ethanol's putative antidepressant response. Ethanol's antidepressant response might have been weaker than that of ketamine, considering ethanol's weaker antagonism of NMDA receptors and stronger stimulation of γ-aminobutyric acid (GABA) type A receptors. ³ Once these patients were addicted, aversive withdrawal symptoms, craving and alcohol-seeking behaviour occurred, which worsened their depression and fuelled more frequent or continuous drinking.

Abstaining alcohol-dependent individuals have lower limbic brain glutamate concentrations than normal controls, ⁵ suggesting a long-term adaptation to too many glutamate surges alongside harmful drinking. Can this also happen to the brain when ketamine is frequently applied, thus giving birth to an aberrant learning process, such as addiction? Moreover, prolonged intake of either ethanol or ketamine is associated with gene expression of specific NMDA receptor subunits, sustained inhibition of synaptic long-term potentiation and decreasing levels of neurotrophins ³ – themselves all related to an addicted brain and precursors to neurotoxicity.

Ketamine and ethanol are good examples of psychoactive drugs, whose wanted – even therapeutic – effects (e.g. the antidepressant response) can silently turn to adverse effects (e.g. addiction or neurotoxicity) after exceeding an individual critical amount and duration of intake. This is based on their ability to use the same pathway to trigger cortico-limbic plasticity involved in the generation of antidepressant response, tolerance and addiction. If at all possible, finding the optimal route of administration and dosing of ketamine to produce a preferably long-term antidepressant response without burgeoning tolerance (even to ketamine's antidepressant response) remains a big challenge. ³