Ketamine: The final frontier or another depressing end?

Abstract

Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.

Keywords: Antidepressant mechanism; Depression; Ketamine; Major Depressive Disorder; NMDA; Non-NMDA mechanism; Rapid antidepressant; Spravato.

Figure 1:. Therapeutic and side effects of ketamine

A. These data are taken from the comprehensive review by Panos et al., 2018. The values shown are inhibitor constant (Ki) of ketamine and its metabolites. They are a range of values taken from different brain tissue or culture systems using different ligands. This table illustrates the lack of knowledge about the action and potency of ketamine and its metabolites in many neurotransmitter systems. (/ Not studied or unknown; ^ Human receptor/transporter)

Figure 2:. Potency of ketamine and its metabolites to various receptor systems in rodents.

A. Ketamine is a versatile drug that induces different effects at escalating doses. Figure 2 shows a few examples of ketamine’s beneficial as well as detrimental properties. Ketamine has a wide range of physiological and cognitive effects at subanesthetic doses (plasma concentrations: <1000 ng/mL). At low plasma concentration of 25–50 ng/mL (0.1 mg/kg, i.v.) there is mild euphoria, and little to no psychoactive effects are experienced. Slightly above those concentrations (50–200 ng/mL or 0.1–0.5 mg/kg, i.v.), analgesic and anti-inflammatory effects take place. The antidepressant effects of ketamine also occur during this time and is associated with enhanced sensory perception and memory deficits. At much higher concentrations (1200–2400 ng/mg or 1–2 mg/kg, i.v.), ketamine induces dissociative anesthesia.

Figure 3:. Proposed intracellular mechanism for ketamine’s antidepressant effect.

A. Panel A- The disinhibition hypothesis: The prevailing hypothesis for ketamine’s (KET) antidepressant action(s) involves its preferential binding to NMDAR on GABAergic interneurons (A1) in the medial prefrontal cortex (mPFC). The inhibition of these interneurons results in reduced tonic inhibition (A2) to glutamatergic neurons and subsequent increase in synaptic glutamate release (A3). Activation of AMPARs by glutamate (A4) increases brain derived neurotrophic factor (BDNF) translation (A5) and released into the synapse to subsequently bind to TrkB receptors (A6). This activates the MAPK (ERK) and PI3K-AKT pathways (A7) known to increase MTOR activity (A8) which, in turn, promotes protein translation (A9) involved in upregulation of AMPARs and spine formation. B. Panel B: The direct inhibition hypothesis: Activation of the synaptic NMDAR (B1) stops the phosphorylation eEF2 (B3) via eEF2K (B2) thus preventing the inhibition of BDNF translation (B4). Panel B: Inhibition of extrasynaptic NMDARS (ex-NMDAR): Ketamine binds to ex-NMDAR disinhibiting tonic activation that suppresses CREB activity (C3), which regulates transcription of synaptic growth and morphological changes. Panel B: Increased serotonergic neurotransmission:Ketamine is known to result in increases in synaptic 5-HT via disinhibition of mPFC glutamate neurons projecting to the dorsal raphé nucleus. The 5-HT neurons projecting back to the mPFC release 5-HT into the synaptic cleft (D1) and activate 5-HT receptors (D2) and subsequently the PI3K-AKT pathway (D3). AKT phosphorylates GSK3β (D4), rendering it inactive, which promotes MTOR activity (D5) and protein translation.

Figure 3:. Proposed intracellular mechanism for ketamine’s antidepressant effect.

A. Panel A- The disinhibition hypothesis: The prevailing hypothesis for ketamine’s (KET) antidepressant action(s) involves its preferential binding to NMDAR on GABAergic interneurons (A1) in the medial prefrontal cortex (mPFC). The inhibition of these interneurons results in reduced tonic inhibition (A2) to glutamatergic neurons and subsequent increase in synaptic glutamate release (A3). Activation of AMPARs by glutamate (A4) increases brain derived neurotrophic factor (BDNF) translation (A5) and released into the synapse to subsequently bind to TrkB receptors (A6). This activates the MAPK (ERK) and PI3K-AKT pathways (A7) known to increase MTOR activity (A8) which, in turn, promotes protein translation (A9) involved in upregulation of AMPARs and spine formation. B. Panel B: The direct inhibition hypothesis: Activation of the synaptic NMDAR (B1) stops the phosphorylation eEF2 (B3) via eEF2K (B2) thus preventing the inhibition of BDNF translation (B4). Panel B: Inhibition of extrasynaptic NMDARS (ex-NMDAR): Ketamine binds to ex-NMDAR disinhibiting tonic activation that suppresses CREB activity (C3), which regulates transcription of synaptic growth and morphological changes. Panel B: Increased serotonergic neurotransmission:Ketamine is known to result in increases in synaptic 5-HT via disinhibition of mPFC glutamate neurons projecting to the dorsal raphé nucleus. The 5-HT neurons projecting back to the mPFC release 5-HT into the synaptic cleft (D1) and activate 5-HT receptors (D2) and subsequently the PI3K-AKT pathway (D3). AKT phosphorylates GSK3β (D4), rendering it inactive, which promotes MTOR activity (D5) and protein translation.