Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies

Abstract

Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It could be also mediated by one or several ketamine metabolites (e.g., (2R,6R)-HNK). The present review focuses on evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN). We will integrate these considerations with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance. Our analyses will help direct future studies to further elucidate the mechanism of action of fast-acting antidepressant drugs, and to inform development of novel, more efficacious therapeutics.

Introduction

Major depressive disorder (MDD) is a serious, debilitating, life-shortening illness and a leading cause of disability worldwide. According to the World Health Organization, about 350 million people are affected by depression, with a higher risk for females than males (WHO, 2012). MDD is also predicted to be the second leading cause of disease burden in 2020 (Murray & Lopez, 1996).

The current most widely prescribed drugs for MDD treatment, i.e., selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), display serious limitations such as the delay between drug administration and antidepressant efficacy. Divergent roles of serotonin (5-HT) autoreceptors and heteroreceptors in modulating responses to antidepressant drugs explain, at least in part, this long delay of action (Nautiyal & Hen, 2017). In addition, an up to 30% of resistance and non-response rate has made these current treatments less reliable (Mrazek, Hornberger, Altar, & Degtiar, 2014). More precisely, the response rates to SSRI antidepressant drugs are about one-third after the initial prescription and up to two-thirds after multiple drug trials.

Ketamine, a non-competitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor (NMDA-R), is a dissociative anesthetic (Krystal et al., 1994). Clinical studies have demonstrated that it displays antidepressant efficacy in treatment-resistant depression (TRD) (Berman et al., 2000; Zarate Jr. et al., 2006). Different methods have been used for staging TRD (Ruhe, van Rooijen, Spijker, Peeters, & Schene, 2012). Each staging method has its own criteria for treatment duration, classes and number of antidepressant trials, as well as severity of depression. Although there is a lack of consensus regarding these criteria of TRD, failure to respond to more than two classes of antidepressant drugs with adequate dosage and for an adequate duration is typically defined as TRD (McIntyre et al., 2014). More than fifty percent of depressed patients meet this definition (Thomas et al., 2013), among them, those taking monoaminergic antidepressant drugs of the serotonergic/noradrenergic class. However, low response rates to the first antidepressant prescription suggest that there are other strategies/mechanisms of action that may help patients with TRD (Duman & Aghajanian, 2012; Kim & Na, 2016). Ketamine could be one of them.

Twelve randomized clinical trials confirmed that ketamine is the only NMDA-R antagonist to date consistently demonstrating antidepressant efficacy in TRD. Its antidepressant effects following an intravenous infusion are both rapid and robust, even though it has a short-lived action. In most cases, most clinical evidence demonstrates significant effects up to one week with subsequent decreases in response at later time points (see meta-analysis reviews: (Caddy, Giaroli, White, Shergill, & Tracy, 2014; Fond et al., 2014; Newport, et al., 2015; Romeo, Choucha, Fossati, & Rotge, 2015; Xu, Hackett, et al., 2016).

Although downstream neuronal adaptations might be involved in its antidepressant activity (Browne & Lucki, 2013; Sanacora, Zarate, Krystal, & Manji, 2008), the exact mechanisms underlying ketamine's effects remain incompletely resolved. Analyzing in detail brain regions and circuitry involved in its mechanism of action is crucial. It has been postulated that ketamine exerts its therapeutic effect with limited direct interactions with 5-HT systems. Our recent studies performed in BALB/cJ mice suggested evidence of activation of 5-HT neurotransmission in the medial prefrontal cortex (mPFC) (Pham et al., 2017; Pham et al., 2018).

The present review will focus on preclinical data regarding cellular and molecular mechanisms of ketamine underlying its antidepressant-like activity rather than clinical data on ketamine's benefits on TRD. Indeed, a lot of clinical reviews have already been published, though many of them have used a small number of patients with TRD (see meta-analyses: (Caddy et al., 2015; Kokkinou, Ashok, & Howes, 2018; Papadimitropoulou, Vossen, Karabis, Donatti, & Kubitz, 2017)). In addition, some clinical and biological predictors of ketamine’s response are often identical to other therapeutics used in MDD; thus, it is critical to identify more specific clinical biomarkers of this response (Romeo, Choucha, Fossati, & Rotge, 2017).

Preclinical studies have begun to elucidate a working mechanism underlying the rapid antidepressant-like activity of ketamine in animal models/tests of anxiety/depression. Specifically, an initial glutamate burst and activity-dependent synapse formation in the mPFC has been shown (Duman & Aghajanian, 2012; Duman, Aghajanian, Sanacora, & Krystal, 2016; Li et al., 2010). Additionally, the involvement of the balance between excitatory (glutamate, 5-HT) and inhibitory (γ-aminobutyric acid - GABA) neurotransmission within the glutamate mPFC/5-HT dorsal raphe nucleus (DRN) circuitry in rodent studies will be addressed here. Since ketamine is comprised of a mixture of two optical isomers: (S)-ketamine and (R)-ketamine, several active metabolites such as (2R,6R)-hydroxynorketamine (HNK) may also potentially make an important contribution to its antidepressant-like activity (Can et al., 2016). Beyond NMDA-R activation, a possible direct activation of α-amino-3-hyroxy-5-methyl-4-isoxazolepropionic acid receptor subtype (AMPA-R) by (2R,6R)-HNK, the main brain active metabolite (Zanos et al., 2016), is also discussed. Lastly, we also discuss the role of several factors, including species, route and dose of administration, and timing of measures (30 min, 24 h or 7 days prior to testing), which may explain some of the inconsistencies described in the literature.