Convergent Mechanisms Underlying Rapid Antidepressant Action

Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycine_B NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR_2/3) antagonists, GABA_A receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

Figure 1. Proposed mechanisms of action of ketamine and other putative rapid-acting antidepressant

(A) Disinhibition hypothesis: ketamine or scopolamine selectively block N-methyl-D-aspartate receptors (NMDARs) or muscarinic acetylcholine receptors (mAChRs), respectively, expressed on GABAergic inhibitory interneurons, causing a decrease in interneuron activity, which leads to a disinhibition of pyramidal neurons and enhanced glutamatergic firing. (B) Negative modulators of GABA_A receptors (GABA_AR-NAMs) directly act to reduce pyramidal neuron inhibition. Evoked released glutamate binds to and activates post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). (C) Role of ketamine metabolites: Ketamine exerts NMDAR inhibition-independent antidepressant actions via the action of its metabolite, (2R,6R)-hydroxynorketamine (HNK), which acts to promote glutamate release (unpublished data) and AMPAR-mediated synaptic potentiation. (D) Antagonists of the group II metabotropic glutamate receptors (mGluR_2/3) disinhibit the tonic blockade of presynaptic glutamate release, thus enhancing synaptic glutamatergic neurotransmission and thus inducing AMPAR activation. AMPAR activation results in enhanced brain-derived neurotrophic factor (BDNF) release, activation of the tropomyosin receptor kinase B (TrkB) receptor, and a subsequent promotion of protein synthesis via the activation of the mechanistic target of rapamycin complex 1 (mTORC1 complex). (E) Inhibition of extra-synaptic NMDARs: Ketamine selectively blocks extra-synaptic GluN2B-containing NMDARs, which are tonically activated by low levels of ambient glutamate regulated by the glutamate transporter 1 (EAAT2) located on astrocytes. Inhibition of the extra-synaptic GluN2B-NMDARs de-suppresses mechanistic target of rapamycin complex 1 (mTORC1) function, which in turn induces protein synthesis. (F) Blockade of spontaneous NMDAR activation: Ketamine blocks NMDAR-mediated spontaneous neurotransmission (miniature excitatory postsynaptic currents – mEPSC), which results in the inhibition of the eukaryotic elongation factor 2 kinase (eEF2K) activity, thus preventing phosphorylation of its eEF2 substrate. This effect subsequently leads to an enhancement of BDNF translation and ultimately protein synthesis. (G) GLYX-13-induced partial activation of NMDARs: Activation of the NMDARs is hypothesized to activate mTORC1 and thus to induce protein synthesis. (H) Inhibition of NMDAR-dependent burst firing activity of lateral habenula (LHb) neurons: ketamine is proposed to decrease excessive NMDAR-dependent burst firing of LHb neurons linked to depressive symptomatology. All hypotheses propose sustained changes in synaptic plasticity, leading to strengthening of excitatory synapses, being necessary for antidepressant responses. Abbreviations: EAAT2, excitatory amino acid transporter 2; GABA, gamma aminobutyric acid; GSK, glycogen synthase kinase