Ketamine and the next generation of antidepressants with a rapid onset of action

Abstract

Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-d-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.

Introduction

Major depressive disorder (MDD) is a serious, recurrent, heterogeneous, and disabling psychiatric illness that affects millions of individuals worldwide, and has a major negative impact on public health and productivity (Baune et al., 2007, Kessler et al., 2006). More than half a century ago, it was observed that the antidepressant imipramine was clinically effective in treating MDD. Since then, a great many other antidepressants have been developed; these are largely similar to imipramine in their mechanism of action, but are more selective. For instance, selective serotonin reuptake inhibitors (SSRIs) are safer and better tolerated than tricyclic antidepressants, but they have not been equivocally shown to offer advantages in terms of efficacy or speed of onset of action. Most surprisingly, recent studies clearly show that antidepressants are of only limited effectiveness for many patients. For example, in the largest open-label study (STAR⁎D) evaluating standard therapies for MDD, less than one-third of patients receiving standard antidepressants experienced remission after up to four months of treatment (Thase et al., 2005, Trivedi et al., 2006). Furthermore, remission in half of the patients often required six months of treatment and two antidepressant trials (Judd et al., 2002, Trivedi et al., 2006).

In addition to the issue of efficacy, the delayed onset of therapeutic effects associated with standard antidepressants is still a major challenge in the treatment of MDD. This is a critical public health problem, because high rates of mortality and morbidity are present during this latency period, and these are associated with a worse long-term course (Machado-Vieira et al., 2008). Furthermore, despite the relatively large number of antidepressants available (Rush et al., 2006, Trivedi et al., 2006), our limited understanding of both the pathophysiology of MDD and the mechanisms of action involved in the therapeutic effects of antidepressants have been significant impediments to developing improved treatments. The key mechanism of action in the effects of standard antidepressants is thought to be their ability to increase monoamines in the synapses. Given that the clinical efficacy of these traditional agents is typically observed only after weeks of treatment, recent theories have suggested that monoamines are only primary effectors, modulating downstream signaling pathways responsible for their therapeutic efficacy (Manji and Lenox, 2000, Payne et al., 2002).

In recent years, it has become increasingly clear that there is an urgent need to develop pharmacological treatments for MDD that exert rapid and sustained antidepressant effects within hours or even a few days. In this context, the finding that the N-methyl-d-aspartate (NMDA) antagonist ketamine induces a rapid antidepressant response within hours has led to exciting new research into cellular mechanisms that affect rapid antidepressant action. Relatedly, accumulating evidence suggests that alterations in the regulation of glutamatergic neurotransmission contribute to the pathophysiology of MDD, as well as to the mechanism of existing antidepressants. This supporting evidence comes from: 1) findings of glutamatergic abnormalities in patients with MDD; 2) effects of existing antidepressants and mood stabilizing medications on the glutamatergic system; 3) preclinical evidence suggesting that drugs targeting various components of glutamate neurotransmission possess antidepressant and anxiolytic properties; and 4) recent studies demonstrating the effectiveness of glutamate-modulating agents in the treatment of mood disorders.

Thus, it appears that agents targeting the glutamatergic system may be key to developing a new generation of improved treatments for this devastating illness. In this article, we describe recent advances in this area with a special focus on the role of ketamine as a proof of concept agent for the development of new, improved treatments for MDD (Sanacora et al., 2008).

Glutamate is a critical excitatory neurotransmitter in the human brain system and is known to play a major role in cellular plasticity and cellular resilience (Sanacora et al., 2008). Diverse clinical studies have supported a critical role for the glutamatergic system in the pathophysiology of MDD, and it is believed to be a key target in mood regulation (reviewed in Maeng and Zarate (2007) ,Sanacora et al. (2008) andZarate et al. (2002)).

Glutamate acts pre- and postsynaptically through the activation of diverse receptors characterized by structural characteristics. Ionotropic glutamate receptors—NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate (KA)—are ion channels that open the channel pore and allow ionic influx to the cell when activated. This influx regulates the neuronal surface's polarization, thus activating intracellular signaling cascades. In contrast, the metabotropic receptors (mGluRs) are G-protein-coupled receptors that directly modulate the second messenger pathways. The mGluRs in group I, including mGluR1 and mGluR5, stimulate the hydrolyzation of phosphoinositide phospholipids in the cell's plasma membrane. The receptors in groups II (including mGluR2 and mGluR3) and III (including mGluRs 4, 6, 7, and 8), with some exceptions, prevent the formation of cyclic adenosine monophosphate (cAMP) by activating a G-protein that inhibits the enzyme adenylyl cyclase, which forms cAMP from adenosine triphosphate (ATP). This review focuses on the ionotropic NMDA and AMPA receptors, which are believed to be directly involved in the antidepressant actions of ketamine (Fig. 1).

The NMDA receptor channel includes the combination of NR1, NR2 (NR2A–NR2D), and NR3 (NR3A and NR3B) subunits. Glutamate's binding site is believed to be in the NR2 subunit, while the NR1 subunit is the binding site for the glutamate co-agonist glycine. Two sites have been identified inside the ion channel: the “s” site, and the phencyclidine (PCP) site; the latter is ketamine's binding site. The AMPA receptors mediate the rapid, desensitizing excitation at most of the synapses, and are responsible for the early synaptic response to glutamate. When activated, AMPA receptors open the pore, thus allowing the influx of sodium and the consequent neuronal membrane's depolarization. The AMPA receptors comprise four subunits (GluR1–GluR4). At mature synapses, AMPA receptors are frequently co-expressed with NMDA receptors, where in concert they contribute to the synaptic plasticity processes involved in learning, memory, and neuroprotection (Malinow & Malenka, 2002).