Searching for ketamine's antidepressant mechanisms: From synaptic plasticity to dentate gyrus cell proliferation

A study led by Dr Henrik Seth provides further evidence linking rapid antidepressant effects with dentate gyrus cell proliferation while hippocampal synaptic plasticity and glutamatergic neurotransmission remain essentially unaltered shortly following an acute low (subanaesthetic) dose of ketamine.1 N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, an arylcyclohexamine that is closely related to phencyclidine (PCP), was discovered in 1962 by Dr Calvin Stevens and was some years later brought into clinical practice as an anaesthetic agent (Figure 1). Due to its dissociative and hallucinogenic properties ketamine was rapidly adopted also for recreational use. Serendipitous clinical findings decades later sparked interest to this fascinating compound in psychiatry. A report published in the year 2000 showed that a subanaesthetic dose of racemic ketamine (0.5 mg/kg, slow intravenous infusion) alleviated core symptoms of depression within just a couple of hours after the infusion and the effects on mood lasted for several days.2, 3 The antidepressant effects of ketamine thus became evident much faster than seen with conventional antidepressant drugs such as serotonin-selective reuptake inhibitors (eg, fluoxetine). These remarkable effects of ketamine, and its S-enantiomer (esketamine), have been since replicated in multiple independent patient trials and the treatment is already in (off-label) use in many countries. Psychoactive effects and abuse potential in particular raise concerns for the widespread use of ketamine in psychiatric patients. To find better alternatives enormous research efforts have been invested to decipher the neurobiological basis underlying ketamine's therapeutic effects. Number of scientific papers within this field has massively increased during the past years (Figure 1). Roughly half of the studies rely on preclinical models, mostly in vitro and in vivo experiments employing laboratory rodents. While several important discoveries have been made, the precise mechanism that explains rapid antidepressant effects of ketamine remains unknown. Prevailing view is, however, that rapid facilitation of glutamatergic neurotransmission and subsequent activation of BDNF (brain-derived neurotrophic factor) receptor TrkB (tropomyosin related kinase B) signalling and consecutive increase in synaptic plasticity and synaptogenesis are important.3, 4 These mechanisms have been associated with the ability of ketamine to directly block NMDARs (extrasynaptic receptors or receptors located within inhibitory interneurons) and/or to indirectly modulate postsynaptic AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) through glutamate surge. Notably, a recent animal report proposes that a non-anaesthetic metabolite of ketamine, the hydroxynorketamine (HNK), is responsible for the antidepressant effects of ketamine through a mechanism involving AMPARs but not NMDARs.5 This hypothesis remains however untested in patients. Moreover, to which extent this metabolite regulates neurobiological processes in the brain that are considered critical for ketamine's antidepressant effects remain poorly studied. Michaëlsson and co-workers have performed a comprehensive set of studies in rodents to investigate the acute effects of racemic ketamine (and HNK)—at subanaesthetic doses—on hippocampal glutamatergic neurotransmission and synaptic plasticity, and dentate gyrus cell proliferation.1 Significant parts of studies were conducted in rats exposed to synthetic glucocorticoid dexamethasone during late prenatal development. This treatment transiently influenced the body weight gain and hippocampal size during postnatal development. Adult animals exhibited behavioural endophenotype reminiscent of depression (reduced sucrose consumption as a measure of anhedonia) that was rapidly normalized by ketamine. Pre-exposure or acute application of ketamine produced unexpectedly modest acute effects on long-term potentiation and baseline glutamatergic neurotransmission in the hippocampal slices obtained at adult age. Perhaps somewhat greater effects were seen in P30 (postnatal day 30) slices but the effects were still marginal and non-significant. Very similar effects (or lack of them) were seen in slices that were obtained from adult rats intraperitoneally injected with ketamine (10 mg/kg), regardless of whether the animals were subjected to dexamethasone treatment or not. To reveal significant effects the authors focused into dorsal or ventral portions of the hippocampus but the end results remained the same. Even the effects of ketamine on the hippocampal expression of the AMPAR/NMDAR subunits were unexpected. While GluA1 and GluN1 levels remained unaltered, GluA4 levels were reduced 24 hours after ketamine injection. These analyses were done however in crude brain homogenates, rather than enriched synaptosomes. The authors thus find limited evidence for altered glutamatergic neurotransmission or synaptic plasticity in response to a single subanaesthetic dose of ketamine. Interestingly, the most obvious effect of ketamine in this study was increased Ki-67 (a marker of cell proliferation) immunoreactivity within the hippocampus 24 hours post-treatment. The effects appeared in all layers of the dentate gyrus but only in animals pre-exposed to dexamethasone. Ketamine (or HNK) had no impact on cell proliferation when directly applied on isolated hippocampal stem cells. This paper together with other recent findings6 thus link the antidepressant effects of ketamine into hippocampal cell proliferation, differentiation and neurogenesis, which are already associated with the mechanism of action of traditional monoaminergic antidepressants. The race of discovering the fundamentals of rapid-acting antidepressant effects of ketamine is currently one of the most exciting areas of neuropharmacology and psychiatry. This excitement is reflected in high publication output (Figure 1) and increasing number of hypotheses.3 This paper is yet another piece of evidence revealing the complexity of the effects of ketamine. The effects of ketamine—and the ability to catch them—may depend on dose, timing, metabolism, strain and age of animals, experimental model (in vitro vs in vivo, naïve animals vs animal models of depression) etc. Yet, currently no consensus holds on even what dose or dosing regimen of ketamine best translates from the clinic to basic research. Notably, in terms of administration route and pharmacodynamic effects the dosing of nitrous oxide ("laughing gas"), another NMDAR antagonist and a putative rapid-acting antidepressant, is very similar between mice and men. Indeed, nitrous oxide was also recently shown to prominently increase hippocampal cell proliferation and brain TrkB signalling.7, 8 In-depth comparative mechanistic studies with such diverse putative rapid-acting antidepressants, not to forget the HNK, are important to carry out in the future. I am sure the race keeps ongoing. University of Helsinki has filed a patent application wherein a novel method for predicting rapid antidepressant effects is disclosed (TR as an inventor).