KADRIU et al., RAPID-ACTING ANTIDEPRESSANTS, MARCH 2019 1 Rapid-Acting Antidepressants Bashkim Kadriu, MD; Subha Subramanian, MD; Zhi-De Deng, PhD; Ioline D. Henter, MA; Lawrence T. Park, MD; Carlos A. Zarate, Jr., MD Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA Abstract Major depressive disorder (MDD) is a highly prevalent and debilitating illness and closely linked to suicide risk. Currently available antidepressants take weeks to work and have low remission rates; indeed, about a third of individuals with MDD fail to fully remit in response to these agents. Novel therapies that target the glutamatergic system—such as ketamine—offer rapid antidepressant effects as well as high remission rates, making them attractive therapeutic options. This chapter reviews the evidence for the antidepressant efficacy of several novel therapeutics, including ketamine, esketamine, nitrous oxide, scopolamine, GLYX-13, and buprenorphine, as well as interventional techniques such as sleep deprivation. Notably, ketamine and esketamine also rapidly reduce suicidal thoughts, making them attractive solutions in an emergency setting. Because studying the rapid onset of antidepressant effects associated with these agents has also improved our understanding of the neurocircuitry and neural signaling systems underlying MDD, some pivotal drug trials using rodents, neuroimaging, and electrophysiological studies are also reviewed. INTRODUCTION Major depressive disorder (MDD) is a highly prevalent condition that affects nearly 20% of the population at some point during their lives. MDD is currently the second leading cause of disability worldwide [1], and the World Health Organization (WHO) has predicted that, by 2020, it will be the number one cause of disability [2]. MDD is also the DSM diagnosis most strongly associated with suicide attempt (53.8%) [3], a phenomenon whose rates have sharply increased over the past two decades in the United States [4]. Current first-line treatment options for MDD include pharmacological agents primarily directed at monoaminergic targets (mostly based on serotonin or norepinephrine) as well as cognitive- based therapies. However, despite the critical role that pharmacological and cognitive therapies KADRIU et al., RAPID-ACTING ANTIDEPRESSANTS, MARCH 2019 2 play in the treatment of MDD, a large proportion of patients remain inadequately treated [5, 6]. Indeed, the large National Institute of Mental Health (NIMH)-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of approximately 4000 outpatients with MDD found that standard pharmacological monotherapy was effective in ameliorating depressive symptoms in only one-third of these individuals [6]. Furthermore, another third of patients failed to achieve remission even after four attempts to change therapeutics, augment medications, or use cognitive behavioral therapy [6], with each attempt lasting 12–14 weeks. These data suggest that a large proportion of individuals with MDD face poor outcomes even with standard treatment. This lack of immediate response—or no response in the case of individuals with treatment-resistant depression (TRD)—coupled with the prolonged period needed to achieve remission even in those who do respond to currently available medications exposes patients to polypharmacy; this trend further underscores the notion that currently available antidepressant treatments are inadequate for many MDD patients. MDD is a complex, heterogeneous condition associated with a multifaceted constellation of symptoms that likely represent divergent biological mechanisms, which complicates treatment algorithms. As noted above, monoaminergic-based treatments such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepres- sants (TCAs), and monoamine oxidase inhibitors (MAOIs) take weeks to months to exert their full antidepressant effects; this lag-time often leads to patients discontinuing their treatment early or relapsing after initial response. Finally, even effective therapeutics used to treat severe TRD, such as MAOIs, are not target-specific and are thus associated with metabolic or cardiac side effects, further decreasing patient compliance and increasing comorbidities. The recent discovery that glutamatergic-based drugs are uniquely capable of rapidly and robustly treating mood disorders has ushered in a new therapeutic era in the quest to develop novel and efficacious antidepressant treatments [7, 8]. This chapter highlights pivotal research into these novel fast-acting pharmacological agents, as well as novel and existing neuromodulatory interventions associated with the rapid alleviation of depressive symptoms. Recent research into the mechanistic underpinnings of these treatment modalities is also described, as these data continue to help the scientific community understand the etiology of MDD and TRD. KADRIU et al., RAPID-ACTING ANTIDEPRESSANTS, MARCH 2019 3 KETAMINE Mechanism of Action of Ketamine Ketamine is a prototypic glutamatergic modulator that acts as a non-competitive, high-affinity, N-methyl-D-aspartate receptor (NMDAR) blocker. Ketamine rapidly increases the number and function of spine synapses [9] and has high lipid solubility and limited protein binding, which allows the brain to rapidly absorb and re-distribute the compound, with a plasma distribution half-life of four to 10 minutes and a terminal half-life of two hours [10, 11]. Over the past two decades, ketamine’s well-documented rapid antidepressant effects (reviewed below) have galvanized efforts to understand its underlying mechanism of antidepressant action. Several broad classifications of this hypothesized mechanism have emerged, including both NMDAR-dependent and independent mechanisms. NMDAR-dependent mechanisms include, but are not limited to: 1) disinhibition of gamma-aminobutyric acid (GABA)-ergic intraneurons driven by presynaptic NMDAR blockade [12]; 2) direct inhibition of extrasynaptic GluN2B-containing NMDARs [13]; and 3) inhibition of NMDAR burst activity coming from the lateral habenula [14]. NMDAR- independent mechanisms include, but are not limited to: 1) conversion of ketamine to its plasma metabolite hydroxynorketamine (HNK), which induces rapid-onset and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput coupled with down- stream signaling changes [15]; and 2) the regulation of glutamate release via the stabilization of excitatory and inhibitory interactions [9, 16]. One model hypothesized that ketamine blocks NMDARs on interneurons in the prefrontal cortex (PFC), which disinhibits pyramidal neurons and leads to a glutamate surge and to AMPA receptor (AMPAR) activation [18]. AMPAR activation then triggers the translation and release of brain-derived neurotrophic factor (BDNF). BDNF, in turn, binds to and activates the tropomyosin receptor kinase B (TrkB) receptor, triggering the activation of the mechanistic target of rapamycin (mTOR)1 pathway and protein synthesis [19]. Another model proposed that ketamine blocks NMDARs at rest, which disinhibits eukaryotic elongation factor 2 (eEF2), promotes BDNF translation, and increases protein synthesis and synaptogenesis [20]. The result is a net increase in BDNF, protein synthesis, and synaptogenesis that reverses chronic stress and neuronal atrophy (see Figure 1). BDNF is a key regulator of synaptic plasticity and has been implicated in the neurobiology of depression [21]. Loosely defined, synaptic plasticity is an adaptive process by which local or KADRIU et al., RAPID-ACTING ANTIDEPRESSANTS, MARCH 2019 4 Figure 1: Proposed mechanisms of action of glutamatergic modulators and other putative rapid-acting antidepressant treatments. Disinhibition hypothesis: Ketamine and esketamine selectively block N-methyl-D-aspartate receptors (NMDARs), and scopo- lamine selectively blocks muscarinic acetylcholine receptors (mAChRs). These are expressed on gamma-aminobutyric acid (GABA)ergic inhibitory interneurons, and their blockade decreases interneuron activity, which leads to a disinhibition of pyramidal neurons and enhances glutamatergic firing. Glutamate then binds to and activates post-synaptic α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The role of ketamine metabolites: (2R,6R)-hydroxynorketamine (HNK) exerts NMDAR inhibition-independent antidepressant actions by activating AMPAR-mediated synaptic potentiation. Other glutamatergic modulators: GLYX-13, which has partial agonist properties at NMDARs, is hypothesized to activate mechanistic target of rapamycin complex (mTORC) and subsequently induce protein synthesis. GLYX-13 requires AMPA and activity-dependent brain-derived neurotrophic factor (BDNF) release, but unlike ketamine does not produce glutamate bursts. AMPAR activation enhances BDNF release, activates the tropomyosin receptor kinase B (TrkB) receptor, and subsequently promotes protein synthesis by activating the mTORC complex. 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 mTORC1 function, which in turn induces protein synthesis. Finally, blockade of spontaneous NMDAR activation inhibits eukaryotic elongation factor