The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

Abstract

The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the "glutamate inhibition" and "glutamate activation" hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.

Keywords: Chronic stress; Depression; Glutamate neurotransmission; Ketamine; Nucleus accumbens; Prefrontal cortex; Rapid-acting antidepressants.

Conflict of interest statement

Conflict of Interest statement

CGA has served as a consultant and/or on advisory boards for Genentech and Janssen, and editor of Chronic Stress for Sage Publications, Inc.;

GS reports personal consulting fees from Alkermes, Allergan, Biohaven Pharmaceuticals, Eli Lilly and Co., Genetech, Janssen Pharmaceuticals, Lundbeck Research USA, Merck & Co., Naurex, Navitor Pharmaceuticals, Noven Pharmaceuticals, Teva Pharmaceuticals Industries, Taisho Pharmaceutical Co., Takeda Pharmaceutical Co, Sage Pharmaceuticals Inc., Sevier, Valeant Pharmaceuticals, and Vistagen Therapeutics Inc.; grants and research contracts from Eli Lilly and Co., Janssen Pharmaceuticals, Merck & Co., and Sevier and support from Sanofi-Aventis, in the form of free medication for an NIH sponsored study over the last 36 mos. In addition, Dr. Sanacora is a stockholder and holds stock options in Biohaven Pharmaceuticals; and has a patent for Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued Jul 15, 2014) with royalties paid from Biohaven Pharmaceuticals; GFM is a consultant for Sumitomo Dainippon Pharma Co. Ltd and UCB Pharma SA, and serves on the Scientific Advisory Board of Elucidata Inc.;

RSD reports no competing interests;

JHK is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, U.S. Patent No. 5,447,948 (issued Sep 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued Jul 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on Mar 5, 2014); U.S. application or Patent Cooperation Treaty international application No. 14/306,382 (filed on Jun 17, 2014);

Published by Elsevier Inc.

Figures

Figure 1. Chronic Stress Pathology (CSP) in the Prefrontal Cortex (PFC)

The synaptic CSP model proposes that synaptic dysconnectivity may be a common pathological pathway across psychiatric disorders with chronic stress component – as a predisposition, a trigger, or an outcome. In the PFC, chronic stress is believed to induce glial deficit, leading to reduced glutamate reuptake capacity and increased extrasynaptic glutamate levels and excitotoxicity. Subsequently, neuronal atrophy develops, resulting in overall reduction in glutamate neurotransmission, which reflects reduced dendritic length and branching, and reduction of spines and synapses density. In the remaining PFC synapses, the neurotransmission strength is also affected by reduced postsynaptic glutamate N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors. Ketamine reverses this PFC CSP within 24h of injection. It is thought that ketamine induces a transient (minutes-to-hours) postsynaptic glutamate activation, which leads to upregulation of neurotrophic signaling, increased protein synthesis, and sustained (days-to-weeks) restoration of synaptic connectivity. Abbreviations: EAAT = excitatory aminoacid transporter; Gln = glutamine; GluN1 = NMDA subtype 1; GluN2B = NMDA subtype 2B; Glu = glutamate. The figure was adapted with permission from the Emerge Research Program (emerge.care).

Figure 2. Molecular Targets of Rapid-acting Antidepressants (RAADs)

It is believed that RAADs exert their effects by inducing a transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. It remains to be determined in future studies whether inhibition of extrasynaptic N-methyl-D-aspartate (NMDA) receptors would be sufficient to exert RAAD effects. The figure depicts the potential targets of agents suspected to have RAAD properties. Abbreviations: AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF = brain derived neurotrophic factor; CB1 = cannabinoid receptor; EAAT = excitatory aminoacid transporter; eEF2 = eukaryotic elongation factor 2; Gln = glutamine; GluN1 = NMDA subtype 1; GluN2B = NMDA subtype 2B; Glu = glutamate; Gly = Glycine; GlyT = Glycine transporter; HNK = hydroxynorketamine; M-AChR = muscarinic acetylcholine receptor; mGluR2/3 = metabotropic glutamate receptor subtype 2 and 3; mTORC1 = mechanistic target of rapamycin complex 1; N-AChR = nicotinic AChR; TrkB = tyrosine kinase B receptor. The figure was adapted with permission from the Emerge Research Program (emerge.care).