Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors

Abstract

Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person's suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl-d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics.

Keywords: NMDA; antidepressants; antipsychotics; dopamine; esketamine; glutamate; ketamine; mood disorders; postsynaptic density; serotonin; suicide.

Figure 1

Complex molecular interactions amongst transductional pathways underlying ketamine antidepressant effects. NMDA receptors blocked by ketamine administration activates a complex downstream signaling, which comprises the entangled interaction among multiple transductional pathways, such as mTORC1-regulated transcription factors, PSD proteins, and calcium-modulated effectors. mTORC1 signaling is activated by AMPAR stimulation induced after NMDA blockade, which in turn may induce a Ca²⁺-mediated BDNF secretion and the subsequent Trk receptor stimulation, thus promoting translation of different factors deputed to the control of cell proliferation, growth and survival. PSD scaffolding proteins (Homer, Shank, PSD-95) connect multiple receptors, such as ionotropic and metabotropic glutamate receptors, as well linking these receptors to intracellular calcium stores. Through PSD proteins, glutamate signaling may intermingle at intracellular level with dopaminergic pathways, and activate GSK3, which may participate in the modulation of mTOR-regulated pathways, thereby affecting cell survival and differentiation. All these transductional pathways converge on appropriate nuclear targets via specific effectors (CaMK, MAPKsm ERK) in order to fine-modulate long-term activity-dependent neuronal rearrangements. NMDAR, N-methyl-d-aspartate glutamate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor; mGluR1a/5, metabotropic glutamate receptor type 1a/5; VDCC, voltage-dependent calcium channel; BDNF, brain-derived neurotrophic factor; Trk receptors, tyrosine kinase receptors; TARP, transmembrane AMPA receptors regulating protein or stargazin; PSD-95, postsynaptic density protein 95kD; DISC1, disrupted in schizophrenia 1; GSK3, glycogen synthase kinase 3; GKAP, guanylate kinase associated protein; H1a, Homer1a immediate-early inducible protein; PIP2, phosphatydilinositol bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; ER, endoplasmic reticulum; PLC, phospholipase C; PKC, protein kinase C; PP2A, protein phosphatase 2A; Akt1, RAC-α serine/threonine-protein kinase; CAMK, calcium-calmodulin regulated kinase; MAPKs, mitogen-activated protein kinases; Erk, extracellular signal-regulated kinase; MEK, MAPK/Erk kinase; Shc, Src homolog and collagen adaptor; Grb2, Growth factor receptor-bound protein 2; Gab1/2, Grb2-associated binder 1; PI3K, phosphoinositide 3 kinase; mTOR, mammalian target of rapamycin; Raptor, Regulatory-associated protein of mTOR; mLST8, mammalian lethal with SEC13 protein 8; p70S6K, ribosomal p70 S6 kinase; 4E-BP, 4E eukaryotic factor binding protein; eIF-4B, eukaryotic initiation factor 4B; EF2K, Eukaryotic elongation factor 2 kinase.