New targets for rapid antidepressant action

doi:10.1016/j.pneurobio.2015.12.001

Progress in Neurobiology

Volume 152, May 2017, Pages 21-37

https://doi.org/10.1016/j.pneurobio.2015.12.001 Get rights and content

Abstract

Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others.

Introduction

Depression directly affects the brain and periphery and is associated with diverse other medical comorbidities due its systemic deleterious effects. The “monoamine hypothesis” of depression – which was developed after observing the pharmacological effects of early drugs for depression – is no longer the only model capable of explaining the mechanism of action of antidepressants or for studying the underlying pathophysiology of depressive episodes in mood disorders.

Currently available conventional antidepressants unfortunately have low rates of treatment response; while one-third of patients with depression will respond to their first antidepressant, approximately two-thirds will respond only after trying several classes of antidepressants (Trivedi et al., 2006). Furthermore, therapeutic approaches must be considered not only in the context of treating acute episodes, but for relapse prevention as well as intervention in the early phases of illness. With regard to conventional antidepressants, few targets besides the monoamines and the hypothalamic pituitary adrenal (HPA) stress axis have been identified as key candidates; nevertheless, the interaction between organs, proteins, hormones, and several comorbid diseases remains complex, and results of studies investigating these targets are preliminary. Thus, there is a strong need to identify and rapidly test novel antidepressants with different biological targets beyond the classic monoaminergic receptors and their downstream targets; these agents would also be expected to act faster in a larger percentage of individuals. However, in recent years the pharmaceutical industry has been investing less in psychiatry and mood disorders as a therapeutic area. This review discusses some of the striking recent advances in the development of novel, rapid-acting antidepressants as well as the potential issues and pitfalls related to research in this field. We also present an overview of the most promising targets and approaches as well as ideas for next steps for drug development.

Section snippets

Rapid onset of antidepressant action

As noted above, currently available monoaminergic antidepressants are associated with a delayed onset of action of several weeks, a latency period that significantly increases risk of suicide and self-harm and is a key public health issue in psychiatric practice (Machado-Vieira et al., 2009c). This concept of a latency period before achieving antidepressant efficacy is widely accepted despite the fact that very few trials have evaluated efficacy outcomes on a daily basis during the first week

Regulation of glutamate ionotropic receptors (NMDA, AMPA) in the context of rapid antidepressant effects: General overview

Glutamate is the main excitatory neurotransmitter in the mammalian brain. Roughly one-third of central nervous system (CNS) neurons use glutamate and, in combination with other excitatory neurotransmitters, it plays a key role in memory, learning, and neuroplasticity (Machado-Vieira et al., 2009b, Machado-Vieira et al., 2012); broadly, the term neuroplasticity includes changes in gene regulation and intracellular signaling cascade, variations in neurotransmitter release, modifications of

AMPA and NMDA receptors: Specific findings in mood disorders research

Preclinical evidence suggests that the glutamatergic system in general – and the NMDA and ionotropic receptors in the tripartite glutamatergic synapse in particular – may be central to both the pathophysiology of MDD and the mechanism of action of antidepressants (Skolnick, 1999, Skolnick, 2002, Skolnick et al., 1996). Most of the evidence pertaining to the pathophysiology of mood disorders supports the presence of increased glutamate levels and activity in the brain and periphery (Zarate et

Ketamine as a proof of concept agent in studies of rapid antidepressant action: Biological models

Ketamine is a noncompetitive antagonist; it binds within the ion channel and blocks the influx of diverse ions. Ketamine is called a “trapping blocker” of the NMDA channel. It acts as a non-competitive NMDA receptor antagonist, which means that it only blocks the receptor when the channel is open after activation. Evidence from different models suggests that several molecular mechanisms are associated with ketamine's plasticity-inducing effects. For instance, studies of diverse proteins and

Ketamine's effects on synaptogenesis, mTOR, and intracellular signaling: Potential therapeutic implications

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates cellular metabolism, growth, and survival as well as protein synthesis and transcription (Duman et al., 2012, Machado-Vieira et al., 2015). The mTOR pathway is altered in other illnesses such as obesity and diabetes, as well as in ageing and stress-related disorders (Zoncu et al., 2011). Reduced mTOR signaling has been observed in the PFC and periphery of subjects with mood disorders (Jernigan et al., 2011,

Other molecular downstream targets for developing rapid antidepressant treatments

As noted above, ketamine's mechanism of action goes beyond simple NMDA antagonism or even activation of the mTOR pathway (Fig. 1). It directly affects other ionic channels such as voltage-operated calcium channels (VOCC), opioid receptors, and AMPA receptors as well as monoamine and muscarinic receptors (Hirota and Lambert, 1996) and other intracellular signaling cascades associated with neuroplasticity. Other pathways associated with rapid antidepressant effects in preclinical models involve

Ionotropic glutamate receptor modulators

Early studies with ketamine (see Niciu et al., 2014 for a recent review) inspired the pharmaceutical industry to develop similar glutamate modulators such as ketamine enantiomers. One key agent with this profile is esketamine, which acts primarily as a non-competitive NMDA receptor antagonist, but is also a dopamine reuptake inhibitor. Phase II studies of esketamine are underway using esketamine in intranasal spray form, a more feasible and rational route of administration when considering

Sleep deprivation

Rapid antidepressant effects have also been observed after a night of sleep deprivation (Bunney and Bunney, 2013), but few studies have shown a potential neurobiological basis for these effects. Approximately half of patients with either MDD or bipolar depression have been found to respond positively to one night of sleep deprivation (Wu and Bunney, 1990). Although some have argued that antidepressant response to sleep deprivation is only transient and therefore not a “real” antidepressant

Translating new targets into new, improved, rapid-acting antidepressants: Perspectives and challenges for future studies

As the above review has underscored, to date the most promising novel targets for achieving rapid antidepressant effects are the ionotropic glutamate receptors. However, to date, no subunit specific modulator has been shown to induce a robust and rapid antidepressant action. Moving forward, predicting response by identifying potential responders a priori will be key to the concept of personalized medicine. Towards this end, the search for the unique biosignatures of rapid-acting antidepressants

Disclosures and role of funding source

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Zarate

Acknowledgements

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. The authors thank the 7SE research unit and staff for their support.

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Published by Elsevier Ltd.

Review articleNew targets for rapid antidepressant action

Abstract

Introduction

Section snippets

Rapid onset of antidepressant action

Regulation of glutamate ionotropic receptors (NMDA, AMPA) in the context of rapid antidepressant effects: General overview

AMPA and NMDA receptors: Specific findings in mood disorders research

Ketamine as a proof of concept agent in studies of rapid antidepressant action: Biological models

Ketamine's effects on synaptogenesis, mTOR, and intracellular signaling: Potential therapeutic implications

Other molecular downstream targets for developing rapid antidepressant treatments

Ionotropic glutamate receptor modulators

Sleep deprivation

Translating new targets into new, improved, rapid-acting antidepressants: Perspectives and challenges for future studies

Disclosures and role of funding source

Acknowledgements

Pharmacol. Biochem. Behav.

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Biol. Psychiatry

Neuropharmacology

Biol. Psychiatry

Cell

Neuropharmacology

Biochem. Pharmacol.

Prog. Neurobiol.

Biol. Psychiatry

Biol. Psychiatry

Neurosci. Lett.

Neuropharmacology

Psychiatry Res.

Biol. Psychiatry

Prog. Neuropsychopharmacol. Biol. Psychiatry

J. Affect Disord.

Cancer Cell

Psychoneuroendocrinology

Biol. Psychiatry

Br. J. Anaesth.

Trends Neurosci.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Brain Res.

Biol. Psychiatry

Eur. Neuropsychopharmacol.

Psychiatry Res.

Brain Res.

Behav Brain Res.

Eur. J. Pharmacol.

Prog. Neurobiol.

Biol. Psychiatry

FEBS Lett.

Med. Hypotheses

Pharmacol. Biochem. Behav.

J. Affect Disord.

Ketamine as a promising prototype for a new generation of rapid-acting antidepressants

Ann. N.Y. Acad. Sci.

Chronotype distribution in bipolar I disorder and schizophrenia in a Korean sample

Bipolar Disord.

Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population

Psychiatr. Genet.

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

Nature

Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder

Hum. Psychopharmacol.

Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model

Behav. Pharmacol.

Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice

Mol. Psychiatry

A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression

Am. J. Psychiatry

AMPA receptors in the therapeutic management of depression

CNS Neurol. Disord. Drug Targets

Review article
New targets for rapid antidepressant action