The Therapeutic Role of d -Cycloserine in Schizophrenia

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The Therapeutic Role of D-Cycloserine in Schizophrenia D. Goff1 NYU School of Medicine, New York, United States 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. A Brief Review of NMDA Receptor Structure and Function 3. History of the Glutamate Model of Schizophrenia 4. Glycine-Site Agonists 5. Early Trials with DCS 6. DCS Added to Second-Generation Antipsychotics 7. Glycine Reuptake Inhibitors 8. D-Serine as a Therapeutic Target 9. Inhibitors of Glutamate Release 10. DCS Pharmacology and NMDA Receptor Subunit Composition 11. DCS Memory Enhancing Effects 12. DCS Effects on Memory in Humans 13. NMDA Receptors and Neuroplasticity 14. DCS and Plasticity 15. DCS and Plasticity in Schizophrenia 16. Conclusion Conflict of Interest References

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Abstract The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl D-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial agonist, D-cycloserine (DCS), aims to enhance plasticity by intermittent treatment. Early trials have demonstrated benefit with intermittent DCS dosing for negative symptoms and memory. When combined with cognitive remediation, intermittent DCS treatment enhanced learning on a practiced auditory discrimination task

Advances in Pharmacology ISSN 1054-3589 http://dx.doi.org/10.1016/bs.apha.2016.02.001

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2016 Elsevier Inc. All rights reserved.

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and when added to cognitive behavioral therapy, DCS improved delusional severity in subjects who received DCS with the first CBT session. These studies require replication, but point toward a promising strategy for the treatment of schizophrenia and other disorders of plasticity.

ABBREVIATIONS DCS D-cycloserine NMDA N-methyl D-aspartate

1. INTRODUCTION The history of D-cycloserine (DCS) and related compounds in schizophrenia over the past 20 years illustrates the evolution of molecular models of schizophrenia and the considerable challenges involved in drug development. The translation of the basic neuroscience of glutamate transmission to schizophrenia therapeutics was pioneered and continues to be led by Joe Coyle (Balu & Coyle, 2015; Goff & Coyle, 2001). A focus on N-methyl D-aspartate (NMDA) receptor hypoactivity as a key mechanism underlying schizophrenia pathophysiology followed from observed similarities between the effects of NMDA channel blockers (phencyclidine and ketamine) and the positive, negative, and cognitive symptoms of schizophrenia. Based on this model, a series of add-on trials were conducted employing agonists at the glycine site of the NMDA receptor, followed by trials of glycine transporter inhibitors. This approach was further supported by evidence suggesting that clozapine’s unique therapeutic efficacy might in part result from effects on glutamatergic transmission. The focus on a hypothesized NMDA receptor deficit was extended to a microcircuit model involving hypoactivity of NMDA receptors located on inhibitory interneurons resulting in disinhibition of glutamate release acting at non-NMDA glutamate receptors (Lisman et al., 2008); this model predicted that reduction of glutamate release by lamotrigine or mGlu2/3 agonists might also produce therapeutic benefit. However, early positive results with glycine-site agonists or inhibitors of glutamatergic transmission have not been replicated consistently, possibly due to the heterogeneity of illness, poor bioavailability of several glycine-site agonists, interactions with NMDA receptor effects of second-generation antipsychotics (Breese, Knapp, & Moy, 2002), the targeting of later-stage illness rather than early-stage illness (Kinon, Millen, Zhang, & McKinzie, 2015), and the increasing problem of failures to

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replicate positive trials in schizophrenia (Rutherford et al., 2014). More recently, genetic studies in large samples of individuals with schizophrenia have implicated a diverse array of more than 100 SNPS associated with neurodevelopment, synaptic plasticity, and inflammation, many of which are shared in common with other neurodevelopmental psychiatric disorders (Hall, Trent, Thomas, O’Donovan, & Owen, 2015; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014), while postmortem studies consistently identify deficits in inhibitory transmission via GABAergic interneurons (Lewis, 2009). These findings suggest that schizophrenia is unlikely to result from abnormal transmission at a single receptor, but rather results from a heterogeneous collection of genetic and environmental factors that disrupt molecular networks that maintain balance between inhibitory and excitatory activity, or between neuroplasticity and neurotoxicity. NMDA receptors may contribute to symptom expression due to their key roles in neurodevelopment, neurotoxicity, and neuroplasticity. In response to this increasingly complex model, pharmacologic approaches are beginning to address developmentally specific mediators of plasticity that may restore homeostasis. At the same time, the relationship of DCS activity relative to NMDA receptor subunit composition has added to the complexity of designing clinical trials and interpreting their results. A large literature has established DCS effects on memory and neuroplasticity; this evidence has led to strategies involving intermittent treatment with DCS in conjunction with cognitive interventions. Exploratory clinical trials in schizophrenia based on these findings have shown promise for negative symptoms, memory impairment, and for enhancement of the cognitive behavioral treatment of delusions.

2. A BRIEF REVIEW OF NMDA RECEPTOR STRUCTURE AND FUNCTION Glutamate is the primary endogenous ligand of NMDA receptors, which gate the opening and closing of cation channels. NMDA receptors are ionotropic glutamate receptors, along with AMPA receptors and kainate receptors—all three bind glutamate and are named after high-affinity selective ligands. Because they open more slowly and for a more sustained period than other ionotropic receptor-gated channels, and are highly permeable to calcium, NMDA channels modulate the functional and structural plasticity of synapses by affecting the threshold for depolarization and by activating calcium-dependent signaling cascades and gene expression. In order to

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conduct calcium, NMDA channels require occupancy of the NMDA receptor site by presynaptic release of glutamate, occupancy of the glycine recognition site by glial release of glycine or D-serine, and partial depolarization of the neuron to dislodge the magnesium blockade of the channel—this convergence of multiple inputs required for channel opening results in NMDA channels serving as “coincidence detectors.” Activation of NMDA receptors is a critical element of brain development, including the activity-dependent preservation of synapses; in addition, NMDA receptors play a critical role in synchronization of brain function by gamma oscillations and in memory by long-term potentiation (LTP). Excessive glutamate transmission, particularly acting at extra-synaptic NMDA receptors, may produce cell injury and death. The majority of NMDA receptors in the central nervous system are heteromeric complexes formed by two obligatory GluN1 subunits and two GluN2 subunits, which include GluN2A, GluN2B, GluN2C, and GluN2D. The composition of NMDA subunits differs between cell types, changes over the course of development, and is highly plastic in response to activity and pharmacologic interventions. The pharmacology of NMDA receptors also differs according to subunit composition; agents selective for specific subunits are in development (Menniti et al., 2013) and a selective GluN2B partial agonist, GLYX-13, has demonstrated efficacy in depression (Burgdorf et al., 2015).

3. HISTORY OF THE GLUTAMATE MODEL OF SCHIZOPHRENIA Kim, Kornhuber, Schmid-Burgk, and Holzmuller (1980) reported decreased cerebrospinal fluid concentrations of glutamate in individuals with chronic schizophrenia and proposed that decreased glutamatergic transmission might play a role in the illness. This finding was supported by some but not all subsequent studies (Bjerkenstedt, Edman, Hagenfeldt, Sedvall, & Wiesel, 1985; Macciardi et al., 1989; Perry, 1982). A decade later, Javitt and Zukin (1991) identified NMDA channel blockade as the mechanism by which phencyclidine and ketamine produced symptoms of schizophrenia. This seminal paper stimulated wide interest in NMDA receptors as a potential treatment target and popularized ketamine as a pharmacologic model for the illness. Experimental administration of phencyclidine to healthy volunteers had begun in the late 1950s (Luby, Cohen, Rosenbaum, Gottlieb, & Kelley, 1959); in recounting this work, Domino and Luby (2012) emphasized that impaired processing of sensory stimuli

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appeared to be a primary component of phencyclidine-induced psychotic and dissociative phenomena, but cautioned that the overlap in symptomatology with schizophrenia was not complete. They and others also demonstrated that phencyclidine exacerbated symptoms in individuals with schizophrenia (Itil, Keskiner, Kiremitci, & Holden, 1967). Krystal et al. (1994) subsequently performed a landmark laboratory investigation of ketamine effects in healthy subjects in which they demonstrated positive, negative, and cognitive symptoms in addition to dissociative effects. Others demonstrated exacerbation of psychosis by ketamine in schizophrenia patients and attenuation of this effect by clozapine but not by haloperidol (Lahti, Koffel, LaPorte, & Tamminga, 1995; Malhotra, Adler, et al., 1997; Malhotra, Pinals, et al., 1997). In addition, ketamine was found to amplify striatal dopamine release in response to amphetamine in healthy subjects in a pattern similar to the increased dopamine release characteristic of schizophrenia (Breier et al., 1998). Consistent with evidence from ketamine studies, a 95% knockdown of the obligatory NMDA receptor GluN1 subunit in mice produced hyperactivity and stereotypies which responded to haloperidol and social withdrawal that only responded to clozapine (Mohn, Gainetdinov, Caron, & Koller, 1999). In addition, postmortem examination of schizophrenia brains found increased concentrations of N-acetyl-aspartyl glutamate (NAAG), an endogenous antagonist at NMDA receptors and inhibitor of glutamate release (Tsai et al., 1995). More recently, kynurenic acid, an antagonist at the glycine site of the NMDA receptor, was found to be elevated in CSF from individuals with schizophrenia (Linderholm et al., 2012).

4. GLYCINE-SITE AGONISTS In response to accumulating evidence suggesting that reduced activation of NMDA receptors might contribute to symptoms of schizophrenia, several groups administered the NMDA co-agonist, glycine, to enhance NMDA channel opening via the glycine modulatory site. The glycine recognition site was targeted because it reduced the risk of excitoxicity associated with direct agonists at the NMDA receptor (Lawlor & Davis, 1992); in addition, unlike glutamate which is rapidly removed from the synapse following presynaptic release, release of glycine and D-serine by glia modulates NMDA opening in response to glutamate binding. Add-on trials of oral glycine 5–15 g/day produced inconsistent results (Costa, Khaled, Sramek, Bunney, & Potkin, 1990; Rosse et al., 1989; Waziri, 1988), whereas Javitt,

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Heresco-Levy, and colleagues reported improvement of negative symptoms with glycine 30–60 g/day in a series of small placebo-controlled add-on trials with additional improvement of positive and depressive symptoms in some studies (Heresco-Levy et al., 1996, 1999; Heresco-Levy, Javitt, Ermilov, Silipo, & Shimoni, 1998; Javitt et al., 2001; Javitt, Zylberman, Zukin, Heresco, & Lindenmayer, 1994). Subsequent small placebocontrolled trials with the glycine-site agonists, D-alanine (Tsai, Yang, Chang, & Chong, 2006) and D-serine (Heresco-Levy et al., 2005; Tsai, Yang, Chung, Lange, & Coyle, 1998), also demonstrated efficacy for the treatment of negative symptoms. However, in two large, multicenter trials of glycine-site agonists, neither glycine nor D-serine was effective for negative symptoms or cognitive impairment (Buchanan et al., 2007; Weiser et al., 2012).

5. EARLY TRIALS WITH DCS We chose to study DCS because, unlike glycine, D-alanine, and D-serine, it readily crosses the blood–brain barrier and, as a partial agonist at the glycine site of the NMDA receptor, poses less risk for neurotoxicity. DCS (4-amino-3-isoxazolidinone) is a cyclic analog of D-alanine produced by the bacterium, Streptomyces orchidaceus, and is FDA approved for the treatment of tuberculosis. DCS is relegated to second-line status for the treatment of tuberculosis because, at antimicrobial doses of 500–1000 mg/day, neuropsychiatric side effects may occur, including depression, psychosis, and seizures. DCS was first manufactured by Eli Lilly in 1969 under the brand name “Seromycin” as a treatment for Mycobacterium tuberculosis; in 2007 Eli Lilly awarded exclusive rights to the Chao Center for Industrial Pharmacy and Contract Manufacturing at Purdue University to ensure the continued availability of DCS for individuals with treatment-refractory tuberculosis. However, in August, 2015 the Purdue Research Foundation sold the manufacturing rights to Rodelis Therapeutics which subsequently increased the price of DCS from $17 to $360 per tablet. In response to adverse publicity, Rodelis returned DCS to the Chao Center for Industrial Pharmacy and Contract Manufacturing and the price has since been reduced to $34 per tablet. DCS has 70–90% bioavailability and is excreted by the kidneys after hepatic metabolism with a half-life of approximately 10 h. Maximal serum concentrations are achieved approximately 2 h following oral administration. DCS penetrates the blood–brain barrier, producing a CSF-to-serum

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concentration ratio varying between 70% and 100%, although data from one study that employed a single 50 mg oral dose suggested a lower ratio (D’Souza, Morrissey, & Abi-Saab, 1994). In an exploratory placebo-controlled dose-finding trial, DCS was added to first-generation antipsychotics in sequential, 2-week escalating dose trials of 5, 15, 50, and 250 mg daily. Videotaped assessments of symptoms were rated in random order, blind to the DCS dose, and revealed a significant improvement of negative symptoms with the 50 mg dose only (Goff, Tsai, Manoach, & Coyle, 1995). Performance on Sternberg’s Item Recognition Paradigm, a test of working memory, also improved with the 50 mg daily dose. In a similar placebo-controlled design, 4-day trials of escalating DCS doses between 5 and 250 mg daily were administered to medicationfree schizophrenia patients; unblinded ratings indicated significant improvement of negative symptoms with a daily dose of 100 mg only (van Berckel et al., 1996). Although both studies found loss of efficacy when the dose was increased to 250 mg/day, identification of an optimal dose was confounded by the potential effect of cumulative duration of treatment resulting from sequential trials. Subsequent studies reported lack of efficacy for negative symptoms and worsening of psychotic symptoms at doses of 100 mg/day (van Berckel et al., 1999), 250 mg/day (Cascella, Macciardi, Cavallini, & Smeraldi, 1994), and 500 mg/day or higher (Simeon, Fink, Itil, & Ponce, 1970) when added to first-generation antipsychotics. The adverse effects associated with DCS doses above 50 mg/day are in marked contrast to trials of once-weekly dosing in anxiety disorders, in which 500 mg was well tolerated and found to be more effective for fear extinction than 50 mg (Ressler et al., 2004). However, this comparison is confounded by intermittent vs daily dosing schedules. In an 8-week, placebo-controlled trial DCS 50 mg/day added to first-generation antipsychotics significantly improved negative symptoms with no effect on positive symptoms or cognition (Goff, Tsai, et al., 1999); response of negative symptoms correlated with increased activation of the left temporal lobe during a verbal fluency task (Yurgelun-Todd et al., 2005). Worsening of psychosis was noted in one subject who recorded the highest DCS plasma concentration. Subsequent trials of DCS 50 mg/day produced mixed results (Duncan et al., 2004; Goff et al., 2005; Heresco-Levy et al., 2002); the most notable failure was the multicenter CONSIST trial (Buchanan et al., 2007) in which neither DCS or glycine improved negative symptoms or cognition compared to placebo when added to predominantly second-generation antipsychotics (Buchanan et al., 2007). However, DCS was significantly more effective than placebo

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for negative symptoms at the one trial site that did not have a large placebo response rate and response to glycine and DCS was significantly greater than placebo in the small number of subjects treated with first-generation antipsychotics. In a meta-analysis performed prior to the CONSIST study, glycine but not DCS achieved statistically significant efficacy for negative symptoms (Tuominen, Tiihonen, & Wahlbeck, 2005), consistent with the expectation that a partial agonist at the glycine site would be less effective than full agonists. However, the CONSIST trial represents the only large head-to-head comparison of DCS with a full agonist (glycine) and failed to detect a difference in efficacy, leaving this question unresolved. There are several factors that may have contributed to inconsistent results in trials of DCS. First, DCS rapidly deteriorates when exposed to humidity (Rao et al., 1968); precautions were not taken to prevent this risk in most previous clinical trials. Second, fixed dosing designs may have resulted in some subjects falling outside a “therapeutic window” of brain concentrations. Third, second-generation antipsychotic agents influence glutamate signaling via 5HT2A antagonism and this pharmacodynamic interaction may reduce DCS effects (Breese et al., 2002). Fourth, DCS efficacy for memory enhancement is lost with repeated dosing (Parnas, Weber, & Richardson, 2005; Quartermain, Mower, Rafferty, Herting, & Lanthorn, 1994); it is unclear whether tachyphylaxis occurs for the response of negative symptoms as well. Finally, it has recently been demonstrated that DCS efficacy for the enhancement of CBT is attenuated when coprescribed with antidepressants, which were not excluded from previous trials and are commonly prescribed to schizophrenia patients with negative symptoms (Andersson et al., 2015). Regardless, the evidence for efficacy of glycine-site agonists for negative symptoms is stronger for the full agonists than for DCS and may be stronger when added to first-generation antipsychotics compared to second-generation antipsychotics, but the lack of consistency in results makes conclusions regarding efficacy for any of these agents uncertain.

6. DCS ADDED TO SECOND-GENERATION ANTIPSYCHOTICS When DCS was added to clozapine in a dose-escalation trial identical to the earlier dose-finding study in subjects treated with first-generation antipsychotics, DCS at a dose of 50 mg daily selectively worsened negative symptoms (Goff et al., 1996). This finding was confirmed in a

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placebo-controlled cross-over trial in which DCS 50 mg/day was added to clozapine (Goff, Henderson, Evins, & Amico, 1999). In contrast, addition of glycine (Evins, Fitzgerald, Wine, Rosselli, & Goff, 2000) and D-serine (Tsai et al., 1999) to clozapine produced no effect on negative symptoms and addition of DCS to risperidone produced a smaller, intermediate improvement of negative symptoms compared to addition to first-generation agents (Evins, Amico, Posever, Toker, & Goff, 2002). This pattern of response suggests that, as a partial agonist at some NMDA receptors, DCS may attenuate clozapine effects that are mediated by activation of the glycine site of the NMDA receptor. Some evidence has suggested that clozapine may increase either glycine ( Javitt, Duncan, Balla, & Sershen, 2005) or D-serine (Tanahashi, Yamamura, Nakagawa, Motomura, & Okada, 2012) concentrations, although this remains speculative. In support of a glutamatergic mechanism contributing to efficacy for negative symptoms of certain second-generation antipsychotics, elevation by olanzapine of brain glutamate and glutamine concentrations measured by magnetic resonance spectroscopy significantly predicted improvement of negative symptoms in patients who were switched from haloperidol (Goff et al., 2002). A relatively large body of evidence demonstrates that antipsychotics have large effects on NMDA receptor subunit expression which varies by antipsychotic type, dose, brain region, and duration of treatment (Segnitz et al., 2011). Second-generation antipsychotic agents in particular affect NMDA receptors, possibly mediated by serotonin 5HT2A antagonism, which may complicate the addition of DCS to second-generation agents (Breese et al., 2002).

7. GLYCINE REUPTAKE INHIBITORS Given the problems with CNS bioavailability of oral glycine and of this hypothesis. Dose finding in rodents and humans with bitopertin suggested an inverted U-shaped dose response curve, with optimal behavioral effects associated with approximately 50% occupancy. The loss of efficacy at higher concentrations may reflect the finding that inhibition of GlyT1 transporters at levels that saturate the glycine binding site have been shown to promote NMDA receptor internalization and reduce glutamate transmission (Martina et al., 2004). At higher concentrations, glycine may also bind to inhibitory glycine receptors in the hippocampus (Zhang et al., 2014). The first add-on clinical trial of bitopertin in schizophrenia produced a small therapeutic

D-serine, the GlyT1 inhibitor, bitopertin, provided a more robust test

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effect on negative symptoms which was not replicated in subsequent trials (Goff, 2014; Umbricht et al., 2014). A recent trial of another GlyT1 inhibitor, AMG 747, was halted due to an adverse event, but produced significant improvement on one of two negative symptom outcome measures. However, several other GlyT1 inhibitor development programs at other pharmaceutical companies have been abandoned and the potential efficacy of GlyT1 inhibition remains uncertain.

8. D-SERINE AS A THERAPEUTIC TARGET In addition to glycine, D-serine is released from astrocytes and plays a major role in hippocampal plasticity. Inhibition of D-amino acid oxidase (DAO) blocks metabolism of D-serine and results in increased D-serine concentrations in the cerebellum, where DAO is found in highest concentrations (Hopkins et al., 2013; Xia et al., 2004). DAO inhibition in rodents increased 24 h recall of fear conditioning and novel object recognition (Hopkins et al., 2013). In a recent placebo-controlled add-on trial in patients with schizophrenia, benzoate, an inhibitor of DAO, produced large improvements in negative symptoms and cognitive performance (Lane et al., 2013). Because DAO is primarily found in the cerebellum and regulates intracellular D-serine concentrations rather than synaptic concentrations, this approach differs from the more direct approach of blocking glycine reuptake with a GlyT1 inhibitor. Synaptic D-serine concentrations are primarily regulated by the alanine–serine–cysteine transporter (Rutter et al., 2007) and, in the hippocampus, by neuronal serine racemase (Ishiwata, Umino, Balu, Coyle, & Nishikawa, 2015). A rigorous test of D-serine elevation in relevant brain regions remains to be validated, although the initial result with benzoate appears promising.

9. INHIBITORS OF GLUTAMATE RELEASE The theory that behavioral effects of ketamine might result from excessive glutamate release resulting from selective blockade of NMDA channels on GABAergic interneurons was supported by the demonstration that agents that inhibit glutamate release, lamotrigine (Anand et al., 2000) and a GluN2/3 agonist, LY354740 (Krystal et al., 2005), both attenuated ketamine psychotomimetic effects in healthy subjects. Clinical trials of lamotrigine and a GluN2/3 agonist pro-drug, pomaglumetad, both

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produced promising early results; pomaglumetad improved positive and negative symptoms comparable to olanzapine in one trial (Patil et al., 2007) but failed subsequent trials (Stauffer et al., 2013), and lamotrine improved positive symptoms when added to clozapine (Tiihonen, Wahlbeck, & Kiviniemi, 2009) but not when added to other antipsychotics (Goff et al., 2007). The clinical profile of response to lamotrigine augmentation has differed from that of glycine-site agonists in that positive symptom response has been prominent and, in the case of lamotrigine, addition to clozapine has been more effective than addition to other agents (Tiihonen et al., 2009). However, since the reliability of these findings is uncertain, we can only conclude that experience with agents that inhibit glutamate release has paralleled glycine-site inhibitors in demonstrating inconsistent benefit while differing in pattern of response. Of note, analysis of trials with pomaglumetad suggested that efficacy may be greatest for individuals who are early in the course of illness, who receive a lower pomaglumetad dose, and who have not had prior exposure to second-generation antipsychotics (Kinon et al., 2015).

10. DCS PHARMACOLOGY AND NMDA RECEPTOR SUBUNIT COMPOSITION The inconsistent results from clinical studies of agents targeting NMDA receptor transmission led to a reexamination of the pharmacology of these agents and to the development of selective allosteric modulators targeting subclasses of NMDA receptors (Menniti et al., 2013). In the case of DCS, a complex picture has emerged. The effects of DCS on NMDA channel opening vary by dose and by NMDA receptor subtype. Dravid et al. (2010) reported that, at saturating concentrations, DCS activity was 65% compared to glycine at NMDA receptors containing GluN2B subunits, and 90% at NMDA receptors containing GluN2A or GluN2D subunits. In contrast, DCS activity was roughly 200% compared to glycine at NMDA receptors containing the GluN2C subunit (Dravid et al., 2010). As a result, DCS is expected to act as a potent agonist at NMDA receptors containing GluN2C subunits, whereas activity at other NMDA receptors is determined by both the DCS concentration and the relative occupancy of the glycine site by endogenous full agonists (D-serine, glycine, and D-alanine), and the endogenous antagonist, kynurenic acid. Under conditions of relatively high occupancy by endogenous glycine-site agonists, DCS would be expected to act as an antagonist at NMDA receptors containing GluN2B

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subunits. Since DCS has a much higher affinity for NMDA receptors containing GluN2C subunits than GluN2B subunits, agonist activity would be expected to be prominent at lower concentrations and antagonist activity at higher concentrations. Activity at NMDA receptors containing GluN2A subunits would be expected to be relatively similar to glycine. The implications of dose-related selectivity by DCS for subpopulations of NMDA receptors are not fully understood. GluN1 and GluN2A subunit expression is decreased postmortem in both schizophrenia and depression prefrontal cortex, whereas GluN2C subunit expression is decreased in schizophrenia only and GluN2B subunit expression does not differ from healthy control brain (Beneyto & Meador-Woodruff, 2008). GluN2Ccontaining receptors, which may be the primary target for DCS at low concentrations, differ from other NMDA receptors in having a higher affinity for glycine, D-serine, and glutamate and less voltage-dependent gating due to reduced Mg2+ binding. GluN2C-containing receptors are also more sensitive to endocytosis in response to activation of the glycine recognition site. GluN2C subunits are located primarily in the cerebellum but also are found in the mediodorsal and reticular thalamic nuclei, on spiny stellate cells in sensory cortex and on inhibitory interneurons in prefrontal cortex and hippocampus (Binshtok, Fleidervish, Sprengel, & Gutnick, 2006; Karavanova, Vasudevan, Cheng, & Buonanno, 2007; Monyer, Burnashev, Laurie, Sakmann, & Seeburg, 1994; Xi, Keeler, Zhang, Houle, & Gao, 2009). In the cerebellum, GluN2C subunits promote cell survival, whereas GluN2A and GluN2B do not (Chen & Roche, 2009). NR2C knockout mice exhibit deficits in fear acquisition and working memory (Hillman, Gupta, Stairs, Buonanno, & Dravid, 2011). A selective GluN2C/GluN2D agonist, CIQ, reversed effects of the NMDA antagonist, MK801, on prepulse inhibition and working memory (Suryavanshi, Ugale, Yilmazer-Hanke, Stairs, & Dravid, 2014). The location of GluN2C subunits on inhibitory interneurons in prefrontal cortex and hippocampus is of interest given evidence that hypofunction of these cells may play a role in schizophrenia (Cohen, Tsien, Goff, & Halassa, 2015). Similarly, the prominence of GuN2C subunits in thalamic nuclei and on spiny stellate cells in layer 4 of cortex, which are targets of thalamocortical input, is of interest in light of growing evidence of dysregulated thalamic oscillations mediated by the reticular nucleus and of impaired thalamocortical connectivity in schizophrenia (Binshtok et al., 2006; Ferrarelli et al., 2012; Zhang, Llinas, & Lisman, 2009). GluN2B subunits, at which DCS is an antagonist, play important roles in LTP and in excitotoxicity (Liu et al., 2007;

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Menniti et al., 2013). Selective antagonism of GluN2B receptors is associated with a loss of memory consolidation and of reversal learning (Rauner & Kohr, 2011), whereas overexpression of GluN2B in rodent forebrain and hippocampus has been associated with improved performance in tests of object recognition and spatial memory (Tang et al., 1999). The enhanced long-term memory associated with GluN2B subunits may reflect the linking of GluN2B subunits to the postsynaptic density, CAMKII and intracellular pathways that mediate plasticity (Shipton & Paulsen, 2014). Microinfusion of DCS in mouse hippocampus increased expression of NR2B subunits and increased proliferation of new and mature neurons in the dentate gyrus (Ren et al., 2013). A single dose of DCS also increased GluN1, GluN2A, and GluN2B expression in medial prefrontal cortex (Gupta et al., 2013). GluN2A subunits, at which DCS acts as a partial agonist with 90% activity, are required for expression of parvalbumin and for gamma oscillations; the number of interneurons coexpressing GluN2A subunits and parvalbumin is decreased in schizophrenia cortex (Woo, Walsh, & Benes, 2004). Finally, DCS reversed social isolation and memory impairment in GluN2D knockout mice, which represents a new model for schizophrenia based in part on the association of the GluN2D gene (GRID1) with schizophrenia (Yadav et al., 2012).

11. DCS MEMORY ENHANCING EFFECTS A large animal literature supports enhancement of learning with DCS (Davis, Ressler, Rothbaum, & Richardson, 2006). Facilitation of both amygdala-dependent and hippocampus-dependent learning has been demonstrated with DCS administration (Monahan, Handelmann, Hood, & Cordi, 1989; Thompson, Moskal, & Disterhoft, 1992). DCS facilitates memory encoding, consolidation, or retrieval in fear conditioning and extinction (Davis et al., 2006), maze tests (Quartermain et al., 1994; Rodgers, Harvest, Hassall, & Kaddour, 2011), spontaneous place recognition (Ozawa, Kumeji, Yamada, & Ichitani, 2012), and foot shock avoidance (Flood, Morley, & Lanthorn, 1992) paradigms. DCS does not affect performance during training, but enhances encoding posttraining as shown by enhancement of recall when administered 20 min after training (Davis et al., 2006). Unlike classic extinction, DCS-enhanced extinction generalizes to other cues (Ledgerwood, Richardson, & Cranney, 2005) and is believed to “erase” the fear conditioning memory rather than enhance a counter-balancing extinction memory. The “erasure” of fear conditioning

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has been associated with inward trafficking of postsynaptic AMPA and NMDA receptors (Mao, Hsiao, & Gean, 2006; Mao, Lin, & Gean, 2008). DCS appears to enhance novel learning only; for example, DCS did not enhance recall of extinction training in animals that had previously received the same extinction training before reinstatement of fear conditioning (Langton & Richardson, 2008). Importantly, DCS effects on learning rapidly diminish with repeated dosing (Quartermain et al., 1994). Five pretreatment doses of DCS attenuated DCS effects on fear extinction; after a period of 28 days, the memory enhancing effects of DCS were fully restored (Parnas et al., 2005).

12. DCS EFFECTS ON MEMORY IN HUMANS Memory enhancement with DCS in humans has received less attention. In healthy subjects, a DCS dose of 50 mg did not enhance hippocampal-dependent declarative memory (Otto et al., 2009), whereas a dose of 250 mg improved encoding of declarative memory such that the threshold for improvement of performance was achieved with only 50% of the number of trials that were required without DCS (Onur et al., 2010). Facilitation of memory encoding by DCS was associated with increased hippocampal BOLD activation (Onur et al., 2010). In another study in healthy human subjects, a single dose of DCS 250 mg before sleep produced a large improvement (effect size d ¼ 0.85) in overnight recall of a declarative memory task (Feld, Lange, Gais, & Born, 2013). DCS 500 mg enhanced 72-h delayed recall of contextual fear extinction in healthy subjects, which was associated with increased activation of hippocampus and medial PFC measured by fMRI (Kalisch et al., 2009). A single 250 mg dose of DCS also improved decision making related to optimizing earning and minimizing loss in a complex learning task (Scholl et al., 2014). In a landmark trial, Ressler et al. (2004) demonstrated that a single dose of DCS 100 or 500 mg before two sessions of exposure therapy significantly improved acrophobia compared to placebo; benefits persisted at 3-month followup. Subsequently, DCS has been found to improve outcomes when combined with CBT for a range of anxiety disorders (Norberg, Krystal, & Tolin, 2008). Benefit was associated with fewer sessions, possibly because DCS accelerates response without increasing the maximal possible improvement from CBT alone. However, a recent meta-analysis of DCS augmentation of CBT found promising results from a few studies but no overall benefit from DCS compared to placebo in 21 studies that were judged to be generally of

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poor quality (Ori et al., 2015). Recently, it has been found that benefit from DCS depends upon the therapeutic effect of individual CBT sessions; both positive and negative responses to therapeutic sessions are “consolidated” by DCS and so the potential benefit of DCS augmentation depends upon the effect of CBT in individual sessions (Smits et al., 2013). In addition, efficacy of DCS for augmentation of CBT for obsessive compulsive disorder was found to be blocked by concurrent treatment with antidepressants, which may have been a prevalent confounding factor in previous studies (Andersson et al., 2015).

13. NMDA RECEPTORS AND NEUROPLASTICITY Adaptation to environmental change or environmental demands, which is broadly referred to as neuroplasticity, is a fundamental brain function. Most simply, this involves learning and memory, although it also includes defending against inflammatory or physical injury and adjusting neuronal activity to enhance performance and conserve energy. NMDA receptors play important roles in plasticity, neurotoxicity, and response to inflammation and stress. The many modulators of NMDA channel opening point to the delicate balance between optimal calcium influx to promote neuroplasticity vs excessive calcium influx which can be neurotoxic via oxidative stress (Hardingham, 2009). Prenatal stress, including mild chronic stress, results in changes in NMDA subunit expression associated with decreased plasticity in adulthood (Li et al., 2014). Similarly, early exposure to maternal immune activation increases both major histocompatibility complex and kynurenic acid; both reduce NMDA function and neuroplasticity (McAllister, 2014). The developmental impact on NMDA receptor protein expression of neonatal exposure to inflammation differs markedly according to the age of exposure and differs between hippocampus and cortex (Harre, Galic, Mouihate, Noorbakhsh, & Pittman, 2008). Genetic studies in schizophrenia have found prominent linkages with genes involved in calcium signaling, neurodevelopment and immune response (Corvin & Morris, 2014), and methylation studies in schizophrenia have found evidence of early exposure to hypoxia and inflammation (Aberg et al., 2014). These findings are consistent with an emerging model of schizophrenia which posits a deficit in neuroplasticity, possibly resulting from early exposure to inflammation or stress coupled with genetic vulnerability (Balu & Coyle, 2012).

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14. DCS AND PLASTICITY DCS may enhance plasticity by producing persistent alterations in NMDA receptor function; this may involve changes in subunit composition as previously discussed, as well as changes in expression of molecules involved in intracellular pathways that mediate plasticity and stimulation of neurogenesis. For example, both DCS and D-serine enhanced LTP in the CA1 hippocampal subfield produced by theta frequency burst stimulation (Hopkins et al., 2013). A single dose of DCS also increased intrinsic excitability and activity-dependent cytoskeletal (Arc) protein expression in CA1 neurons consistent with increased neural plasticity (Donzis & Thompson, 2014). Plasticity requires BDNF release and is inhibited by inflammation. DCS reversed the effect of decreased BDNF expression on extinction learning in adolescent rats (McCallum, Kim, & Richardson, 2010; Pattwell et al., 2012) and also rescued impaired extinction memory in mice with a genotype associated with reduced BDNF release (Yu et al., 2009). This interaction appears to be reciprocal, since BDNFreleasing antidepressants attenuated DCS effects on extinction memory (Werner-Seidler & Richardson, 2007). Following closed brain injury in mice, a single dose of DCS elevated hippocampal BDNF concentrations and was associated with more rapid neurologic recovery (Yaka et al., 2007). DCS was also found to reverse memory impairment produced by immune activation (Kranjac et al., 2013). In humans, DCS has been shown to increase plasticity as measured by transcranial direct current stimulation (tDCS) (Nitsche et al., 2004) and by EEG response to high-frequency visual stimulation (Forsyth, Bachman, Mathalon, Roach, & Asarnow, 2015).

15. DCS AND PLASTICITY IN SCHIZOPHRENIA While clinical measures of plasticity are quite limited, evidence from several approaches support reduced plasticity in schizophrenia brain. Memory consolidation, as represented by 24 h delayed recall, has been found to be impaired for fear extinction and procedural memory tasks (Holt, Coombs, Zeidan, Goff, & Milad, 2012; Manoach et al., 2010). Studies in which plasticity is stimulated by repeated transcranial magnetic stimulation or tDCS have found deficits in schizophrenia independent of medication status (Voineskos, Rogasch, Rajji, Fitzgerald, & Daskalakis, 2013). We administered a single dose of DCS 50 mg prior to administering the Logical Memory Test of the Wechsler Memory Scale (Wechsler, 1997), in

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which the subject is asked to recall facts (items) and themes after hearing a brief narrative. We found significant improvement in recall of story themes after a 7-day delay compared to placebo (Goff et al., 2008). No improvement was found in immediate recall or in recall of specific items. This finding is consistent with sleep-associated memory consolidation in which the “gist” of new learning is transferred to long-term memory (Chatburn, Lushington, & Kohler, 2014). We also found that once-weekly administration of DCS for 8 weeks significantly improved negative symptoms measured 7 days after the last DCS dose in two placebo-controlled studies (Cain et al., 2014; Goff et al., 2008). Although the sample sizes were small (n ¼ 19 and 38) these results are promising, particularly since most subjects were treated with second-generation antipsychotics. The observation that intermittent dosing of DCS may produce persistent neuroplastic changes is consistent with the hypothesis that tachyphylaxis may be avoided by minimizing NMDA receptor endocytosis and that synaptic strength (LTP) may be enhanced by increased expression of NGlu2B subunits. We also studied the combination of once-weekly DCS 50 mg and cognitive remediation in an 8-week trial (Cain et al., 2014). Compared to placebo, once-weekly administration of DCS 50 mg produced significantly greater improvement on the auditory discrimination exercise of the cognitive remediation program. However, cognitive enhancement did not generalize to tasks that were not practiced—subjects who received DCS displayed no improvement on the MATRICS cognitive battery, whereas the placebo group significantly improved on the MATRICS composite score compared to baseline and on the visual memory domain of the MATRICS battery compared to the DCS group. This finding requires replication but suggests that the cognitive improvement with DCS reflects activity-dependent synaptic plasticity rather than generalized neuroplasticity and so only practiced cognitive tasks benefit. Finally, in a pilot cross-over trial in 21 schizophrenia patients with treatment-resistant delusions, DCS 50 mg or placebo were administered in random order before two sessions of a CBT exercise that promotes cognitive flexibility in the interpretation of delusional beliefs (Gottlieb et al., 2011). Subjects who received DCS prior to the first CBT session displayed significantly greater improvement in ratings of delusional severity and associated distress compared to subjects who received placebo first. We currently are examining this approach in a larger, parallel design; however, the results are consistent with evidence that DCS selectively enhances novel learning and hence would be expected to augment the first, novel CBT session to a greater degree than the second, nonnovel session (Langton & Richardson, 2008).

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16. CONCLUSION An initial focus on the NMDA receptor in schizophrenia has evolved to embrace a more complex view of schizophrenia as resulting from dysregulation of networks dependent upon NMDA activity, including neurodevelopment, neuroplasticity, and synchronization. A loss of neuroplasticity secondary to NMDA receptor downregulation could follow from early exposure to potentially neurotoxic stimulation of NMDA receptors from stress or maternal inflammatory reactions. Rather than correcting a deficit of transmitter at the glycine site of the NMDA receptor, new approaches aim to restore plasticity via intermittent dosing with agents like DCS or with allosteric modulators selective for NMDA subunit subtypes, much as intermittent dosing with ketamine and the GluN2B partial agonist, GLYX 13, have been used in depression (Burgdorf et al., 2015; Zarate et al., 2006). Schizophrenia appears to respond quite differently to drugs acting at the NMDA receptor complex compared to individuals with depression or anxiety disorders. In schizophrenia, low doses of DCS which may selectively activate NMDA receptors containing the GluR2C subunit appear to be most effective; higher doses may produce worsening of psychosis. DCS doses of 100 mg or higher, at which antagonism of NMDA receptors containing GluR2B subunits may prevail, have been associated with worsening of psychosis, consistent with the sensitivity of individuals with schizophrenia to the psychotomimetic effects of NMDA receptor channel blockade with ketamine. In addition, intermittent treatment may be more effective than daily dosing by avoiding tachyphylaxis; the GluN2C subunit confers increased susceptibility to endocytosis with repeated dosing. In contrast, intermittent treatment with DCS 500 mg is well tolerated and effective in individuals with anxiety disorders and intermittent treatment with ketamine is therapeutic in refractory depression. It is hoped that the promising results from early experiments with single or intermittent dosing with DCS in schizophrenia will be replicated in larger trials and that enhancement of learning could facilitate psychosocial rehabilitation in this often disabling illness.

CONFLICT OF INTEREST The author has no conflict of interest to declare. The author receives research support from the NIMH, Stanley Medical Foundation and Avinar Pharmaceuticals and has received no honoraria over the past 5 years.

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