**3. The Neurobiological and Psychological Effects of Ketamine**

When administered at subanaesthetic doses, dissociative and mild psychological effects emerge within 15 min [23]. Psychological effects can include dissociation, alterations in perception, depersonalisation and derealisation, amongst others. These effects are transient and usually resolve within 90 min [24]. The antidepressant effects are rapid after the psychological effects dissipate, with effects on depressive symptoms persisting for a week in some patients [24]. This temporal sequence may indicate neuroadaptation to the effects of ketamine in the brain [25]. This aligns with studies revealing the positive influence of ketamine on neuroplasticity and, specifically, synaptogenesis.

Whilst ketamine is an NMDA receptor antagonist, its molecular action is more complex than a simple blockade of NMDA receptors. In fact, at low doses, ketamine paradoxically stimulates glutamate transmission [26]. This is achieved by both increased glutamate release and also increases in AMPA receptors at synapses, which are ionotropic transmembrane glutamate receptors [26]. This, in turn, causes increases in brain-derived neurotrophic factor (BDNF) release, which stimulates the mammalian target of rapamycin (mTOR) via Atk (protein kinase B) and ERK signalling. mTOR is a protein kinase that is important for the control of protein translation and contributes to long-lasting synaptic plasticity by increasing the number and density of synapses. Thus, the positive effect of ketamine on synaptogenesis is thought to reverse the reduced synaptic density that results from chronic stress and depression [27,28] and is implicated in its antidepressant effects.

As well as increasing synaptogenesis, rodent studies have indicated that ketamine increases neurogenesis and downregulates stress-induced inflammation. Adult neurogenesis refers to the birth of new neurons from stem cells, which occurs at a high rate in the hippocampus and is mediated by growth factors such as BDNF and vascular endothelial growth factor (VEGF). Studies in rodents have demonstrated increases in neurogenesis after ketamine administration both in vitro [29] and in vivo [30,31], which is thought to contribute to its sustained antidepressant effects [31]. Similarly, increases in BDNF and VEGF in the medial prefrontal cortex (mPFC) and hippocampus following ketamine administration are thought to contribute to this increase in neurogenesis [32].

Ketamine has also been shown to attenuate stress-induced inflammatory responses in rats. In one study, rodents exposed to chronic unpredictable mild stress exhibited greater hippocampal levels of proinflammatory cytokines (interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α), which were reduced following a low dose of ketamine [33]. Notably, another study found decreases in proinflammatory cytokines in rodents exposed to stressors following ketamine administration but did not observe a reduction in corticosterone [34]. Thus, these effects may be independent of stress hormones. Whilst studies in humans are scarce, these findings have been replicated in patients with depression, with several studies finding decreases in various proinflammatory cytokines after ketamine treatment [35–37]. Whether the anti-inflammatory and antidepressant properties of subanaesthetic ketamine administration are related is debated, with some studies finding an association [36,37] and others finding no association [35,38]. Whilst more research is needed, it is possible that reductions in inflammation partially contribute to the therapeutic effects of ketamine.
