The mechanism of action underlying ketamine’s antidepressant effects

The mechanism of action underlying ketamine’s antidepressant effects

Ketamine affects multiple neurotransmitter systems, including the opioidergic, monoaminergic, glutamatergic, and muscarinic systems, as well as substance P and sigma receptors. Early work by Skolnick and colleagues implicated the glutamatergic system in depression [7], and research over the past three decades further implicated the NMDA receptor in modulating the molecular and cellular processes important for synaptogenesis and neuroplasticity [8].

A recent study demonstrated that blockade of NMDA-dependent burst activity in the lateral habenula (LHb) mediated antidepressant-like effects in animals [9], and neurochemical and functional imaging studies have also corroborated that ketamine treatment partly reverses the glutamatergic and gamma-aminobutyric acid (GABA)-ergic dysfunction previously identified in individuals with depression [10]. Given ketamine’s potent NMDA receptor antagonism, its antidepressant properties were thought to be related to this activity and to a resulting increase of glutamate tone at the synapse. However, the precise mechanism of ketamine’s antidepressant activity remains elusive, and other receptor systems may also be involved.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor [11], metabotropic glutamate receptor (mGluR) [12, 13], and opioidergic [14] signaling pathways have all been implicated in ketamine’s antidepressant properties. In addition, a growing literature has implicated the role of inflammation in MDD, and ketamine’s anti-inflammatory properties have thus gained increased consideration as another mechanism potentially underlying its antidepressant effects [15]. AMPA receptor activation in particular has been shown to modulate downstream factors, such as enhancing brain-derived neurotrophic factor (BDNF) release, which activates the tropomyosin receptor kinase B (TrkB) receptor and, subsequently, mammalian target of rapamycin complex 1 (mTORC1) [16]. Current evidence suggests that a convergence of multiple pathways may best explain ketamine’s unique therapeutic effects [17] (summarized in Fig. 1). Buy Ketamine Powder

figure 1
The mechanism of action underlying ketamine’s antidepressant effects

Variable action of ketamine’s enantiomers and respective metabolites on NMDA and AMPA receptors adds to the challenge of elucidating ketamine’s particular antidepressant effects [18], and additional downstream molecular and cellular pathways have been investigated to better understand ketamine’s rapid-acting antidepressant properties and its effects on promoting neuroplasticity [10].

In preclinical animal model studies, the ketamine metabolites (2S,6S;2R,6R)-hydroxynorketamine (HNK) were found to be essential for its rapid antidepressant effects. In addition, the antidepressant effects of the (2R,6R)-HNK enantiomer were independent of the NMDA receptor, supporting the role of AMPA receptor activity in the potentiation of excitatory synapses in mood-relevant brain regions [11]. In addition, both preclinical and clinical studies have demonstrated sex differences in the antidepressant efficacy and side effect profile of ketamine and its metabolites, further underscoring its pharmacokinetic complexity [19, 20]. Further investigations to better characterize the function of ketamine’s metabolites may lead to better isolation of its antidepressant effects with a reduced side effect profile.

A manuscript will review the clinical evidence for single-dose IV ketamine administration as well as intranasal esketamine for the treatment of MDD and TRD. A review of ketamine’s use for other psychiatric diagnoses, its potential adverse effects, and attempts to prolong its effects with combined therapy or repeated dosing will also be discussed. Finally, current treatment guidelines for ketamine’s clinical use are discussed.

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