Rapid antidepressant effects: moving right along

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1 Molecular Psychiatry (2013), 1 8 & 2013 Macmillan Publishers Limited All rights reserved /13 PERSPECTIVE : moving right along K Martinowich 1,2,3, DV Jimenez 1, CA Zarate Jr 4 and HK Manji 5 Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl-D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response. Molecular Psychiatry advance online publication, 21 May 2013; doi: /mp Keywords: BDNF; depression; ketamine; rapid-acting antidepressant; slow-wave activity; synaptic potentiation INTRODUCTION Depression is a common psychiatric illness associated with high morbidity, recurrence, chronicity, increased mortality and enormous public health cost. 1,2 Suicidal ideation and behavior are particularly concerning aspects associated with major depressive disorder (MDD) as suicide is the third leading cause of death in individuals aged years. MDD is a heterogeneous clinical syndrome characterized by the core symptoms of pervasive, sustained low mood and/or loss of interest in the environment, accompanied by a host of other symptoms, including alterations in sleep and sleep patterns, energy levels, psychomotor function and cognition, as well as significant impairment in ability to function. Depression is estimated to affect at least 120 million individuals worldwide and is a leading cause of disability according to the World Health Organization. Although the rate of antidepressant use has risen dramatically, drug discovery and the advent of new classes of antidepressants have fallen sharply. Despite a burgeoning public health burden from stress-related and depressive disorders, the pace of therapeutic discovery has significantly lagged behind other areas of medicine. This is a serious problem because less than a third of patients with major depression attain remission when administered currently available antidepressants. 3 5 In the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, half of the participants in the study did not respond to an initial antidepressant treatment. 6 Additional treatments in the STAR*D study led only to modest gains in remission rates with 33% of patients remaining ill following after up to four consecutive treatment steps that included antidepressant combination as well as augmentation strategies. These and additional studies have underscored the fact that currently available antidepressants are associated with low remission rates, multiple, often intolerable side effects, frequent relapse and delayed treatment response (requiring anywhere from 2 10 weeks for remission). 7 9 This lag time is especially dangerous and unacceptable, because it is associated with documented high risk for suicidal behavior. 10 FEASIBILITY OF DEVELOPING A RAPID-ACTING ANTIDEPRESSANT Several lines of evidence provide strong proof of principle that it is possible to design therapies with rapid-acting antidepressant effects. First, sleep-deprivation therapy (SDT) has been documented in numerous studies to provide very rapid (within h) clinical relief from depression. Results after SDT are impressive; over 80 studies have described the ability of SDT paradigms to offer both rapid and robust alleviation of depressive symptoms in up to 60% of patients Despite the promising initial effects of SDT, its usefulness as a first-line treatment is impeded by the high rates of relapse observed after subsequent sleep cycle(s). However, because of its robust clinical effects, researchers and clinicians are probing the ability to design a first-rate combination treatment by harnessing the initial effects of SDT coupled with add-on treatments to achieve sustained remission. 16 Second, the switch process in bipolar disorder between the state of depression to its opposing state of mania or hypomania can occur very rapidly. Switching from depression to mania/hypomania can occur spontaneously, but it can also be precipitated by exposure to stress and glucocorticoids, sleep deprivation, electroconvulsive therapy (ECT), some classes of antidepressants as well as exposure to stimulants such as amphetamine. 17 These treatment-emergent switches may be particularly informative by providing insight into the molecular mechanisms driving the switch from a depressive state to a manic/ hypomanic state. 17 Understanding the molecular and cellular bases of these switches could provide key information about mechanisms that allow for extremely rapid changes in affect. This information would be extremely useful for effective development of rapid-acting therapeutics. Third, patients undergoing ECToftenshow initialrapid effects. Although these effects wear off quickly, they gradually build up over a full course of ECT that leads to a more sustained antidepressant effect. 11 Unfortunately, despite the extremely high efficacy of ECT in severely depressed patients, our knowledge of the mechanisms that underlie the ability of ECT to provide relief remains rudimentary. 1 Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4 Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA and 5 Global Therapeutic Area Head, Neuroscience, Janssen Research and Development, Titusville, NJ, USA. Correspondence: Dr HK Manji, Global Therapeutic Area Head, Neuroscience, Janssen Research and Development, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA. HManji@its.jnj.com Received 2 October 2012; revised 25 February 2013; accepted 18 March 2013

2 2 These three lines of evidence suggest that it should be possible to shift the cardinal symptoms of mood very rapidly. However, our currently available treatments fall well short of this goal. One possibility is that currently available treatments are working upstream of the therapeutic targets that directly mediate a response, resulting in the substantial delay to remission. Directly acting on those cellular and molecular targets mediating the therapeutic response should help to overcome the limitations of currently available treatments and provide rapid relief. POTENTIAL CELLULAR AND MOLECULAR TARGETS FOR RAPID EFFECTS Hyman and Nestler 18 presented the theory of Initiation and Adaption as a framework for understanding the effects of psychotropic drugs. This proposal suggested that psychotropic drugs have primary molecular targets that initiate alterations in brain function, which then activate homeostatic mechanisms. Cellular signaling cascades are activated to bring the system back to homeostasis, which ultimately results in achievement of a new adaptive state. In the case of currently used antidepressants, the therapeutic response arises as a result of changes in functional activity of key neural circuits that are misregulated in the depressed state. This new adaptive state is achieved downstream of repeated activation of cellular signaling cascades and biochemical alterations. 18 This theory may help explain why our current drugs are not effective when given occasionally or when not given enough time to work. Although misregulation of the same key neural circuits may be driving the emergence of depressive symptoms, there are likely many ways to achieve the same circuit alteration. Hence, important questions are: (1) how do we figure out what the key downstream targets are? and (2) how can we bypass the dysfunctional adaptive stages and get directly to the relevant downstream target(s)? Since the initial proposal of this theory, our knowledge on cell signaling cascades, particularly in conjunction with stress-related disorders and in the functioning of antidepressants and mood stabilizers, has exploded. Numerous targets within multiple cellular signaling cascades have been implicated, and a significant number of these have pointed to downstream effects on alterations in synaptic plasticity and structural remodeling at the synapse In conjunction with the explosion in knowledge on biochemical and cell signaling cascades, our understanding of the basic neurobiological mechanisms underlying synaptic plasticity and synaptic remodeling have increased dramatically. 19 N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptors are ionotropic glutamate receptors that are expressed throughout the central nervous system where they have been found to have a key role in regulating glutamatergic signaling that controls signaling and plasticity at excitatory synapses. AMPARs mediate fast, excitatory transmission, and the trafficking of AMPARs in and out of the post-synaptic membrane has been closely linked to synaptic strength and plasticity. Numerous preclinical and clinical studies have provided insight into the role of the glutamatergic system in the pathophysiology as well as the treatment of mood disorders. 22 These studies have led to the notion that glutamatergic transmission and resulting dynamic changes in synaptic plasticity may have a role in the treatment response; hence numerous preclinical studies are focusing on agents that target the glutamatergic system (reviewed in Machado-Vieira et al. 23 ). KETAMINE AS A RAPID-ACTING ANTIDEPRESSANT Early work proposed that NMDAR antagonists could serve as a new class of antidepressants based on the finding that exposure to inescapable stress leads to disruption in a type of hippocampal synaptic plasticity dependent on NMDAR signaling. 24 Preclinical work led to the observation that several NMDAR antagonists showed antidepressant effects in rodent models. 24 Extension of this work demonstrated that chronic administration of traditional antidepressants led to changes in NMDAR signaling, suggesting that this signaling pathway might be the common functional mediator of the observed antidepressant effects. These data, in conjunction with findings that disrupted glutamatergic transmission downstream of changes in NMDAR signaling may be implicated in depression, 20,25 led to the rationale to target the NMDAR complex directly as a strategy for improved, faster acting agents in clinically depressed populations. 25,26 In humans, an initial trial in subjects with MDD found that ketamine rapidly improved depressive symptoms within 72 h post infusion. 27 A subsequent double-blind, placebo-controlled, crossover study confirmed this finding, showing that a single ketamine infusion in patients with treatment-resistant depression (TRD) had rapid and relatively sustained antidepressant effects. 28 Similar findings have since been reported in an additional controlled trial, 29 and more recently, two controlled trials in bipolar depression showed the onset of antidepressant effects of a single infusion of ketamine within 1 h. 30,31 It is important to note that the subjects participating in these latter three studies were treatment-resistant, many having failed to achieve remission after multiple antidepressant trials as well as after ECT, arguably the most effective treatment for depression. The improvements in depression seen with ketamine target core symptoms and are fairly sustained, lasting up to several weeks. 32 This is in stark contrast to a single intravenous infusion of the stimulant d-amphetamine where the predominant change is psychomotor activation, elation and a decrease in blunted affect but which has no significant impact on feelings of guilt or anxiety. Moreover, unlike the results with ketamine, amphetamine administration leads only to short-lived improvements in symptoms, which are usually confined to the duration of the drug s half-life (B12 h). 33 ADDITIONAL COMPOUNDS WITH RAPID-ACTING ANTIDEPRESSANT QUALITIES Controlled trials have clearly demonstrated that ketamine can exert rapid and robust antidepressant effects. 27,28 The NMDARs are tetrameric proteins comprising NR1 and NR2 subunits; four different NR2 subunits (NR2A D) exist in the brain. Searching for compounds that can modulate the NMDA receptor complex may be an effective approach to achieve rapid onset of antidepressant effects but limit potential adverse effects. Such a strategy could include use of low-affinity, subunit-specific antagonists and compounds that target allosteric sites in the receptor complex. In particular, more specific targeting of the NR2A and NR2B subunits has been pursued in the development of novel antidepressants. A significant reduction in NR2A and NR2B subunit expression was found in the prefrontal cortex (PFC) of patients with MDD relative to controls, 34 and preclinical models have suggested antidepressant efficacy with antagonists selective for these subunits. Memantine is a low-to-moderate affinity NMDA antagonist that showed promising antidepressant properties in preclinical animal models and in an open-label trial in depressed patients. 38 However, a controlled study did not find antidepressant properties with memantine (20 mg day 1 ) in individuals with MDD. 39 It is possible that higher doses may have resulted in efficacy, but at dosage 420 mg day 1 memantine becomes non-selective for the NMDA receptor. The selective NR2B antagonist Ro was found to activate the mammalian target of rapamycin (mtor), a protein that has been linked to the antidepressant effects of ketamine 40 and, in preclinical rodent studies, was found to have significant antidepressant-like properties. 40,41 Recently, the NR2B subunit selective NMDAR antagonist CP-101,606 was tested in Molecular Psychiatry (2013), 1 8 & 2013 Macmillan Publishers Limited

3 MDD. In this seminal double-blind, randomized, placebocontrolled, add-on trial, a single infusion of CP-101,606 showed early antidepressant effects (at day 5) in patients with TRD who had not responded to a selective serotonin reuptake inhibitor. Dissociative effects were modest and resolved within 8 h but nevertheless resulted in a reduction of the dosage and duration of the infusion. 42 Another, small, randomized, double-blind, placebocontrolled, crossover pilot study similarly found that daily doses of an oral formulation of the selective NR2B antagonist MK-0657 (4 8 mg day 1 ) had significant antidepressant effects on secondary efficacy measures as early as day Finally, Zarate et al. 44 found that the low-trapping NMDA antagonist AZD6765, which acts on mixed NR2A/2B receptors, had rapid antidepressant effects in 22 subjects with TRD. Although the antidepressant effects were short-lived, there was no difference from placebo on adverse psychotomimetic or dissociative effects. 44 Hence, it has now been shown that a broad NMDA receptor (that is, ketamine), the more selective antagonists targeting the NR2B subunit (i.e. CP101,606 and MK-0657) and a low-trapping NMDA channel blocker with effects on a mixed population of NR2A/2B receptors (that is, AZD6765) all can exert rapid antidepressant effects. Together, such results provide evidence in support of the notion that modulating the NMDA receptor complex is a feasible strategy for developing antidepressant therapeutics. Two controlled trials have demonstrated that intravenous scopolamine, a muscarinic antagonist, results in fairly rapid antidepressant effects, described to be significant within 3 days of the infusion. 45 Scopolamine has also been reported to modulate NMDA receptor function. Blocking muscarinic receptors with scopolamine was found to reduce mrna levels of transcripts encoding NMDAR types 1A and 2A in the rat brain in vivo and to protect hippocampal neurons from glutamatemediated neurotoxicity in vitro, 46,47 which could result in reduced NMDAR function. Chronic treatment with tricyclic antidepressant drugs and repeated electroconvulsive shock has also been shown to reduce cortical NMDAR function (reviewed in Krystal et al. 48 ). Taken together with evidence that abnormal glutamatergic transmission is involved in the pathophysiology of depression, these data support the hypothesis that scopolamine s rapid antidepressant effect may occur indirectly via NMDAR antagonism. POTENTIAL CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THE ACTION OF RAPID-ACTING ANTIDEPRESSANTS The neurobiological mechanisms underlying the ability of ketamine to provide antidepressant relief are more complex than its known ability to block NMDARs acutely. The sustained effects of ketamine are apparent well beyond the time when ketamine levels in the brain are able to mediate NMDAR blockade. The low doses of ketamine used in clinical trials first produce transient psychomimetic and dissociative effects B30 min after administration. 28 However, these effects disappear by 80 min 28 ; ketamine s half-life is only 180 min in humans. 49 Early studies using higher, albeit subanesthetic, doses than those used to achieve preclinical and clinical antidepressant effects had demonstrated that ketamine resulted in rapid increases in extracellular glutamate levels in the rodent PFC. It was speculated that this process could be mediated by presynaptic NMDARs and/or by the influence of antagonizing NMDARs on inhibitory GABAergic (gamma-amino-butyric acid) interneurons However, this prevailing theory has been questioned in the context of the antidepressant effects of ketamine for several reasons, including the need for reconciliation between differences in doses required for the increase in extracellular glutamate levels versus the low doses used for antidepressant response. In addition, tonic glutamatergic transmission would be expected to activate AMPARs. However, as discussed in more detail below, AMPAR activation is actually required for the synaptic and behavioral effects of ketamine. Moreover, neither pharmacologically induced disinhibition nor a potentiation in neuronal activity per se is sufficient to trigger a rapid antidepressant behavioral response. 53 These concerns highlight the need for better understanding the specific molecular and cellular sequelae leading from NMDAR antagonism with low doses of ketamine to the observed synaptic effects thought to be involved in its efficacy. For several reasons described below, current research has centered on understanding how the initial effects of antagonizing the NMDA receptor translate into sustained changes in glutamatergic signaling associated with synaptic strength and plasticity. Glycogen synthase kinase-3 (GSK3) has also been implicated in mediating the effects of ketamine. 54 Ketamine s inhibition of GSK3 was necessary for the antidepressant effects of ketamine in a rodent model of depression. 54 Administration of the GSK3 inhibitor lithium, at much higher than normally utilized dosages, produces a rapid antidepressant effect similar to that seen with ketamine administration. 54 This is of particular interest because the antidepressant effects of lithium have been previously shown to depend on potentiated AMPAR signaling. 55,56 Rapid initial antidepressant effects have not been observed clinically with lithium administration; however, rapid inhibition of GSK-3 at the level used in this report would not be feasible as the resulting serum levels (41.5 meq l 1 ) would result in severe toxicity. However, if rapid and sufficient inhibition of GSK-3 is key to the rapid antidepressant effects of ketamine, these limitations could be overcome with administration of potent, small molecular inhibitors that can rapidly inhibit GSK-3 in the brain. The increase in extracellular glutamate levels in response to acute ketamine administration leads to stimulation of AMPARs, which triggers long-term cellular and antidepressant behavioral responses to ketamine. 40,41 The exact sequence of cellular and molecular events leading from NMDAR antagonism (for example, ketamine) to potentiation of glutamatergic signaling and AMPAR activation has not been fully delineated. However, relevant synaptic effects and behavioral responses attributed to ketamine administration are inhibited when AMPARs are blocked. 40,41 Ketamine administration has been shown to decrease spontaneous firing of GABA interneurons in the PFC and leads to a delayed increase in the firing rate of pyramidal cells, 57 which suggests that antagonism of NMDARs expressed on GABAergic interneurons leads to attenuation of spontaneous firing, in turn, leading to pyramidal cell disinhibition and increased glutamate release. This transient increase in glutamate is thought to contribute to the effects of ketamine on synaptogenesis. 40,58 A single subanesthetic dose of ketamine rapidly increases the density of functional synaptic spines in the rodent medial PFC. 40 This effect on synaptogenesis is preceded by a transient increase in mtor signaling and is followed by a prolonged increase in synaptic proteins. Moreover, these effects occur concurrently with an antidepressant effect that lasts for 41 week. 40 The authors of that report demonstrated that these effects are blocked by intracerebroventricular administration of rapamycin, 40 which disrupts activation of mtor and its downstream effects on dendritic translation of synaptic proteins. 59 Although the authors found increased expression of synaptic proteins as early as 2 h following ketamine administration, they observed that this translated into an increase in the number of mushroom (that is mature) spines 24 h after ketamine administration. Confirming the ability of ketamine to potentiate spine function and stability, it was demonstrated that serotonin and hypocretin-induced excitatory post-synaptic currents in layer V of the PFC showed increased frequency and amplitude, suggesting that ketamine leads to an increase in both cortico-cortical and thalamo-cortical connections. 3 & 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 1 8

4 4 Figure 1. Potential cellular and molecular mechanisms underlying the rapid-acting antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) blockade. (1) Pharmacological blockade of the NMDA receptor. Various agents with pharmacological properties leading to NMDAR antagonism have been demonstrated as having rapid antidepressant effects. The NMDAR is an ionotropic glutamate receptor that is both ligand and voltage dependent and is non-selective to cations. The flux of calcium through the NMDAR has been demonstrated as having a crucial role in synaptic plasticity. (2) Changes in glutamatergic transmission. Changes in neurotransmission downstream of NMDAR blockade are thought to contribute to changes in synaptic potentiation and efficacy that are implicated in the antidepressant effects of NMDAR blockade. The disinhibition hypothesis has suggested that blocking the tonic NMDAR-induced firing of GABAergic (gamma-amino-butyric acid) interneurons leads to general disinhibition of glutamatergic pyramidal cells, and a subsequent increase in excitation and synaptic efficacy. 50 The increased glutamate release from pyramidal cells is hypothesized to contribute to AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid) receptor activation and activity-dependent release of brain-derived neurotrophic factor (BDNF). 40,41,102 Another theory posits that administration of NMDAR antagonists leads to blockade of NMDAR activation normally triggered by spontaneous neurotransmission. The selective suppression of this form of NMDAR activation by spontaneous release of glutamate is hypothesized to contribute to inability to activate eukaryotic elongation factor 2 (eef2) kinase, which subsequently results in attenuation of eef2 phosphorylation and de-repression of BDNF translation 53,80 (depicted in (3)). (3) Dendritic spine remodeling/synthesis. Structural remodeling at the synapse is implicated downstream of the changes in glutamatergic transmission and induction of local, dendritic protein synthesis. The upstream changes in glutamatergic signaling due to disinhibition of GABAergic interneurons and inhibitory tone are thought to contribute to activation of the mammalian target of rapamycin (mtor) signaling pathway, which is important in controlling the translational machinery. 40 In this scenario, NMDAR blockade activates signaling via the mtor pathway, contributing to an increase in local dendritic translation of proteins important in dendritic spine synthesis and synaptic remodeling, including structural components at the synapse and the neurotrophin BDNF. 103 (4) BDNF secretion and TrkB activation. Secretion of BDNF leads to signaling through its cognate receptor TrkB; signaling cascades downstream of TrkB activation are implicated in dendrite complexity, spine synthesis and remodeling, synaptogenesis and various forms of synaptic plasticity. TrkB-mTOR signaling also contributes to feed-forward stimulation of synaptogenesis by increasing synaptic protein synthesis, including that of BDNF. 85,103 (5) BDNF trafficking. The BDNF Val66Met polymorphism impacts trafficking of BDNF and its subsequent secretion. Specifically, the Met allele impairs transport of both BDNF mrna transcripts as well as BDNF protein, contributing to a decrease in activity-dependent BDNF secretion (6) Mood-related circuitry and rapid antidepressant effects. Alterations in synaptic plasticity and synaptogenesis may converge to increase synchronization and strength of key, mood-related circuits in the corticolimbic system. Targeting these key connections is thought to underlie the ability to effect rapid and sustained antidepressant efficacy. Follow-up studies by the same group demonstrated that ketamine rapidly reverses the cellular and behavioral deficits resulting from exposure to chronic unpredictable stress (CUS). 58 CUS results in anhedonia, a core symptom of depression, which is responsive to chronic, but not acute administration of traditional antidepressants. 60 At the cellular level, CUS results in decreased spine density and dendritic retraction in rodent PFC and hippocampus Remarkably, a single dose of ketamine was able to rapidly reverse the CUS-induced deficits in depressive-like behavior as well as the deficits in expression levels of synaptic proteins, spine number and the frequency/amplitude of excitatory post-synaptic currents. 58 The authors confirmed their previous results implicating mtor signaling 40 by showing that the effects of ketamine on reversing CUS-induced cellular and behavioral deficits were blocked by previous administration of rapamycin. 58 Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is a key signaling molecule in the central nervous system and has been implicated in the regulation of cell Molecular Psychiatry (2013), 1 8 & 2013 Macmillan Publishers Limited

5 survival, neurogenesis, synaptic strength and plasticity as well as neuronal circuit assembly and refinement. BDNF signaling has been linked to the etiology of depression and implicated in the action of traditional antidepressants. Importantly, several recent landmark reports have established that BDNF has a critical role in contributing to the synaptic plasticity mechanisms underlying the antidepressant effects of ketamine and other NMDA receptor antagonists. 53,65 BDNF is an established mediator of activitydependent synaptic plasticity; it is critical for long-term potentiation as well as the establishment and refinement of cortical circuits during neurodevelopment Notably, decreases in the expression of BDNF have been identified in the PFC and hippocampus as well as other brain regions in individuals with mood disorders, 67,69 71 and the expression of BDNF is increased in depressed patients after administration of antidepressants. 72,73 Deletion of the gene encoding BDNF in mouse models attenuates behavioral responses to antidepressants and infusion of BDNF into either the ventricles or the hippocampus causes rapid and sustained antidepressant effects Collectively, these data have given rise to a neurotrophin hypothesis of major depression. 69 Work from the Monteggia laboratory provided the first compelling evidence that BDNF signaling may be a key factor in mediating the rapid antidepressant actions of ketamine. 53 This report confirmed the rapid antidepressant effects of ketamine in several rodent models and went on to show that these effects were dependent on the rapid synthesis of BDNF. Ketaminemediated NMDAR antagonism leads to deactivation of the eukaryotic elongation factor 2 (eef2) kinase, resulting in attenuation of eef2 phosphorylation. These events allow for derepression of BDNF protein translation and subsequent increase in BDNF protein levels, which are required for the antidepressant actions of ketamine as well as other NMDAR antagonists. 53 Confirming a key role for eef2 signaling in mediating the rapid antidepressant effect, eef2 kinase inhibition results in rapid antidepressant behavioral effect, similar to that of ketamine. 53 These experiments also significantly contribute to illuminating the signaling mechanisms downstream of ketamine that lead to the sustained changes in synaptic transmission that may be important for mediating the longer-term antidepressant actions subsequent to initial NMDA receptor blockade. Importantly, the effects of ketamine-mediated NMDA receptor blockade at rest, which lead to deactivation of eef2 kinase, attenuation of eef2 phosphorylation and BDNF derepression, could not be replicated simply by altering in vivo neuronal activity levels. These results suggest that spontaneous release of glutamate and subsequent NMDA receptor activation that occur independently of action potential firing are a key contributor to ketamine action. 80 This is important because numerous studies have indicated that spontaneous, rather than evoked glutamate release, is important for homeostatic synaptic plasticity by leading to initiation of signaling cascades that contribute to network stability and maturation, local dendritic translation, especially of the neurotrophin BDNF, and control of postsynaptic sensitivity. 80,81 Further elucidation of the role of BDNF signaling downstream of NMDA receptor blockade and its contribution to rapid-acting antidepressant effects has come from investigation of the impact of a nonsynonymous single nucleotide polymorphism in the human BDNF gene (Val66Met), which results in a valine to methionine substitution in the probdnf protein at the sixty-sixth codon of the coding exon. This single nucleotide polymorphism impairs activity-dependent secretion of BDNF 82,83 and reduces trafficking of BDNF mrna to principal cell dendrites. 84 Expression of dendritic BDNF may be particularly important in the context of mechanisms underlying rapid-acting antidepressants because it has been observed that application of BDNF to isolated dendrites results in increased local, dendritic translation, 85 a process which is critical for spine remodeling and synthesis, synaptogenesis and induction of synaptic plasticity. A knock-in mouse model of the human BDNF Val66Met polymorphism has been previously developed, 86 and recent studies show that mice carrying the Met allele show constitutive dendritic atrophy at distal apical dendrites and impaired excitatory post-synaptic currents in layer V pyramidal cells of the medial PFC. Moreover, these animals show decreased dendritic spine density and diameter, suggesting that the Met allele alters normal BDNF function in promoting and/or maintaining synaptogenesis. 65 In addition, these authors showed that normal BDNF function is required for the previously demonstrated effects of ketamine on synaptogenesis 40 as this effect is markedly attenuated in Met/Met mice. The antidepressant behavioral effects of ketamine were also blocked in Met/Met mice, suggesting that these effects are dependent on normal BDNF function. 65 These results were extended to the clinical population in a very recent study reporting that MDD patients with the Val/Val BDNF allele are more likely to exhibit a robust antidepressant response to ketamine than BDNF Met carriers. 87 BDNF signaling has been implicated in synaptic homeostasis, which is mechanistically linked to the induction and build up of slow wave activity (SWA), defined as the power of the Hz oscillations observed on electroencephalogram, that occurs during non rapid-eye movement sleep. SWA has been identified as a macro-electrophysiological readout of synaptic strength, plasticity and network synchronization Expression of BDNF increases during the wake cycle, decreases across the sleep cycle and shows a robust increase in response to sleep deprivation BDNF was first implicated in sleep homeostasis with the observation that the rising expression of BDNF during development is correlated with the onset of increased SWA in response to sleep deprivation. 93 A causal relationship between BDNF and induction of SWA was established with the finding that administration of exogenous BDNF to the cortex potentiated SWA while pharmacologically blocking endogenous BDNF signaling attenuated SWA. 96 Moreover, it was recently demonstrated that genetically altered mice with disrupted activity-dependent BDNF signaling show a reduction in basal levels of SWA as well as decreased SWA potentiation in response to sleep deprivation. 97 Importantly, a recent report has provided evidence linking BDNF function in humans with levels of SWA. 98 Specifically, it was shown that human carriers of the BDNF Met allele of the Val66Met polymorphism show decreased sleep intensity as measured by sleep slow wave oscillations. 98 The link between BDNF, synaptic activation and antidepressant response to ketamine was strengthened by a series of reports in clinical populations demonstrating that successful antidepressant response to ketamine infusion in TRD patients was correlated with BDNF plasma levels and the levels of SWA in the subsequent night following ketamine infusion. 99 In summary, the antidepressant effects of ketamine, and other NMDA receptor antagonists, are due to changes in synaptic function, which may, at least in part, be mediated by the effects of BDNF on synaptic plasticity and potentiation (Figure 1). Previous research has suggested that these increases in BDNF signaling and the resulting synaptic potentiation should lead to increased network synchronization and hence, subsequent increases in SWA. As SWA has been proposed as a marker of central synaptic plasticity, its potentiation following putative antidepressant administration may provide an excellent biomarker for activation of BDNF signaling and initiation of feed-forward plasticity. In addition, it has been well established that sleep deprivation, a known rapid antidepressant therapy, leads to robust increases in BDNF and SWA in the subsequent sleep period. 96 ECT is also known to potently activate BDNF levels, 92,94 and the induction of SWA in the PFC following a course of ECT is linked to its efficacy. 100,101 Thus, the extent or intensity of SWA in the night following administration of putative antidepressant agents or treatment could potentially serve as a readout of induced synaptic potentiation in cortico-limbic circuits that are important in 5 & 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 1 8

6 6 mediating the rapid antidepressant response. Future studies should determine in both rodent models and clinical populations whether synaptic potentiation in response to these agents leads to increased sleep intensity in the following period and whether this is correlated with better behavioral outcomes. Although changes in synaptic potentiation in key cortico-limbic circuits that are misregulated in depression are likely having a key role in mediating the acute effects of rapid-acting agents, the ability to sustain these effects is probably mediated by longerterm alterations, including structural remodeling of synapses and other neuroplastic changes. Indeed, the downstream effects of mtor signaling that have been implicated in ketamine s antidepressant response alter synaptic signaling as evidenced by changes in excitatory post-synaptic currents. Understanding the mechanisms underlying these structural neuroplastic changes is critical for designing novel therapeutics that are both rapid acting as well as sustainable. For example, SDT has robust acute behavioral effects, but relapse often occurs after rebound sleep. In their synaptic homeostasis theory, Tononi and Cirelli 88 postulate that the build-up of synaptic potentiation over the waking day or in response to sleep deprivation is discharged by induction of slow oscillations during sleep. Although SWA could serve as a biomarker for the induction of necessary synaptic potentiation, it may also have a role in relieving the build-up of synaptic strength that was needed for the initial rapid effect. Hence, determining which compounds or which combinations of compounds can be used to harness both the very rapid effects and the neuroplastic/structural events that are necessary to sustain the effects are key for future development strategies. CONCLUSIONS AND FUTURE DIRECTIONS Glutamatergic NMDAR antagonists, specifically ketamine, have emerged as promising candidates to build upon in delivery of the next generation of fast-acting antidepressants. As reviewed here, research is moving quickly to determine the mechanisms that underlie the ability of ketamine to effect its antidepressant actions. This research is serving as a valuable tool by helping to identify biomarkers predictive of response that are so urgently needed for the development of rapid-acting antidepressants. In addition to the NMDAR antagonists, other targets of glutamatergic transmission are being examined. As reviewed above, the behavioral effects of ketamine rely on AMPAR activation, and hence, drugs capable of activating AMPARs directly may be capable of producing rapid and robust antidepressant actions. Another major target of current drug research are presynaptic metabotropic glutamate type 2/3 receptors (mglur 2/3), which have a key role in regulating synaptic glutamate release. The recent studies implicating synaptic mechanisms downstream of ketamine are compelling and offer an array of potential targets for the development of fastacting antidepressants. The dendritic protein translational machinery itself as well as the BDNF transcripts that are available at the synapse for local, dendritic production are particularly noteworthy candidates. Rapidly acting antidepressants hold the possibility of fundamentally changing the way depression is treated and offer tremendous opportunities to clinicians and the patients whom they treat to provide rapid relief. A challenge for the next round of research will be determining whether these rapid-acting compounds can be used for routine treatment in depressive disorders. If rapid-acting antidepressants can be safely moved into routine clinical care, they could provide a host of beneficial effects, including reducing health-care costs by shortening inpatient hospital stays, reducing mortality rates by decreasing suicide and preventing lost productivity arising from missed school and work days. CONFLICT OF INTEREST KM and DVJ are currently full-time employees of the Lieber Institute for Brain Development, CAZ is currently a full-time employee of the intramural program of the National Institute of Mental Health and HKM is currently a full-time employee of Janssen Research and Development, LLC. We declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity for research or professional service and there are no real or perceived financial holdings that could be perceived as constituting a potential conflict of interest. CAZ and HKM are listed as co-inventors on a patent application for the use of ketamine in major depression. CAZ and HKM have assigned their rights on the patent to the US government but may share a percentage of any royalties that may be received by the government. HKM, however, will waive any such royalties that may be received in relation to this patent application. REFERENCES 1 Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. Am J Psychiatry 2006; 163: Baune BT, Adrian I, Jacobi F. Medical disorders affect health outcome and general functioning depending on comorbid major depression in the general population. J Psychosom Res 2007; 62: Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. 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