Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

Abstract

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

Keywords: anxiety; depression; drug repositioning; esketamine; glutamate; suicide.

FIGURE 1

Chemical structure of ketamine stereoisomers and metabolites that can be formed following ketamine infusion in humans.

FIGURE 2

Schematic representation of some potential mechanisms involved in the antidepressant actions of ketamine. (1): Ketamine reduces NMDA receptor mediated stimulation of GABA interneurons reducing the inhibitory action on presynaptic glutamatergic neuron; (2) the reduced inhibition produces a rapid glutamate burst acting on AMPA receptors located on pyramidal neurons; (3) Such activation leads to the opening of voltage-dependent calcium channels (VDCC) that stimulate BDNF; (4) BDNF induce the translation and synthesis of key synaptic proteins in synaptogenesis and maturation of dendritic spines, including GluA1 and PSD95), via the TrkB/Flk-1 - mTORC1-signaling pathway; (5) ketamine acting as NMDA inhibited the eukaryotic elongation factor2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and increased BDNF translation and protein synthesis; (6) ketamine metabolite can stimulate AMPA receptors independently of NMDA receptor blockade by ketamine; (7) kainate receptor can contribute to Na⁺ and Ca⁺⁺ entry, neuronal depolarization and postsynaptic responses.

FIGURE 3

Schematic representation of several major glutamatergic input pathways on mammalian brain nuclei where ketamine might interact with glutamate transmission by interacting with NMDA and/or AMPA receptors. Abbreviation: PFC, prefrontal cortex; Cg25, subgenual cingulate region; Th, thalamus; Hipp, hippocampus; LHb, lateral habenula; Amy, amygdala; VTA, ventral tegmental area; DR, dorsal raphe; BFCS, basal forebrain cholinergic system; LC, locus coeruleus; GP, glubus pallidus. Glutamate (Glu), dopamine (DA), GABA, acetylcholine (Ach), norepinephrine (NA) and serotonin (5-HT) neurons and axons are represented.