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Schizophrenia Bulletin Advance Access originally published online on July 19, 2007
Schizophrenia Bulletin 2007 33(5):1120-1130; doi:10.1093/schbul/sbm083
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© The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Recent Advances in the Development of Novel Pharmacological Agents for the Treatment of Cognitive Impairments in Schizophrenia

Robert W. Buchanan1,2, Robert Freedman3, Daniel C. Javitt4, Anissa Abi-Dargham5 and Jeffrey A. Lieberman6
2 Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 2128
3 Department of Psychiatry, University of Colorado Health Sciences Center
4 Department of Psychiatry, Nathan Kline Institute for Psychiatric Research, New York University School of Medicine
5 Department of Psychiatry, New York State Psychiatric Institute
6 Department of Psychiatry, College of Physicians and Surgeons, Columbia University


   Abstract
Top
 Abstract
Introduction
 Cholinergic Agents
 Dopaminergic Agents
 Glutamate
 Conclusion
 References
 
Wayne Fenton was a major driving force behind the establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) project mechanisms. These projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified 3 drug mechanisms of particular interest: cholinergic, dopaminergic, and glutamatergic. The TURNS project is designed to select potential cognitive-enhancing agents and evaluate their potential efficacy in the context of proof of concept or clinical efficacy trials. This article reviews the rationale for these 3 approaches and provides an update on the development of therapeutic agents, which act through one of these 3 mechanisms.

Keywords: cognitive impairments / nicotinic receptors / dopamine / glutamate


   Introduction
Top
 Abstract
 Introduction
Cholinergic Agents
 Dopaminergic Agents
 Glutamate
 Conclusion
 References
 
People with schizophrenia are characterized by a broad range of cognitive impairments. Areas of impairment include attention/information processing, problem-solving, processing speed, verbal and visual learning and memory, and working memory.1 Despite appropriate treatment with either first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs),2–4 people with schizophrenia continue to exhibit pronounced cognitive impairments. The lack of marked cognitive benefit of antipsychotics has led to the investigation of alternative agents and mechanisms for the treatment of these impairments.

In order to facilitate the development of new pharmacological approaches for the treatment of cognitive impairments in schizophrenia, Wayne Fenton, Ellen Stover and colleagues developed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS; PI: Stephen R. Marder, MD) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS; PI: Stephen R. Marder, MD) project mechanisms. The MATRICS project (http://www.matrics.ucla.edu) was designed to identify core cognitive impairments in schizophrenia, identify promising targets for drug development, develop a battery to assess cognition in clinical trials, and develop study design guidelines for clinical trials of cognitive-enhancing agents. The TURNS project (http://www.turns.ucla.edu) is a network of academic sites charged with selecting potential cognitive-enhancing agents and evaluating their potential efficacy in the context of proof of concept or clinical efficacy trials.

In a 2-day conference, the MATRICS Neuropharmacology Committee identified leading targets for the treatment of cognitive impairments.5 The selection was based on consensus opinion of academic and industry experts. The top candidates were from the following 3 classes: (1) cholinergic agents, including {alpha}7-nicotinic agents; (2) dopamineric agents, including D1 agonists; and (3) glutamatergic agents, including agents that act at either the ionotropic or metabotropic receptors. The current article provides an update on the current status of drug development in each of these classes.


   Cholinergic Agents
Top
 Abstract
 Introduction
 Cholinergic Agents
Dopaminergic Agents
 Glutamate
 Conclusion
 References
 
Introduction
Acetylcholine acts at muscarinic and nicotinic cholinergic receptors. These receptors are broadly distributed throughout the brain, including the neocortex, hippocampus, thalamus, and basal ganglia.6 These regions are part of various neural circuits that subserve simple and complex cognitive processes. The cholinergic system has been implicated in the regulation of attention, memory, processing speed, and sensory gating7–9; processes that are impaired in schizophrenia. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. Postmortem studies have demonstrated alterations in muscarinic receptor and nicotinic receptor availability or expression.10–15 In a recent single-photon emission computed tomography study, muscarinic receptors were significantly reduced in the cortex, thalamus, and basal ganglia of people with schizophrenia.16 Acute nicotine administration has been shown to improve attention, eye tracking, sensory gating, verbal and visual memory, and working memory in people with schizophrenia.17–25 In combination, these studies suggest that people with schizophrenia may have multiple abnormalities of the cholinergic system and that agents, which enhance cholinergic function may act as cognitive enhancers.

{alpha}7-Nicotinic Agents
A series of {alpha}7-nicotinic cholinergic receptor agonists have been developed in an attempt to further characterize central nervous system (CNS) cholinergic function and as potential candidates for the treatment of schizophrenia. Pfizer has a drug development program concentrating on azabicyclic aryl amides.26 The {alpha}7-selective agonist DMXB-A, 3-[(2,4-dimethoxy)benzylidene]-anabaseine, is one of a series of anabaseine compounds developed by William Kem's laboratory at University of Florida.27,28

Convergent neurobiological and genetic evidence has implicated the {alpha}7-nicotinic receptor in the pathophysiology of schizophrenia and hence a potential therapeutic target. Nicotine is heavily abused by people with schizophrenia, an observation that has sometimes been explained as an attempt at self-medication. About 80% of people with schizophrenia smoke, with a mean consumption of 30 cigarettes/d; per cigarette, they extract 50% more nicotine than other smokers.29 Higher nicotine levels are consistent with activity at {alpha}7 receptors, which are less sensitive to nicotine than {alpha}4ß2 nicotinic receptors, the other common neuronal nicotinic receptor that is found on presynaptic terminals of many different neuronal types. Nicotine has positive neurocognitive effects in schizophrenia, particularly on attention, which are consistent with the relationship between diminished sensory gating and attention dysfunction. However, these effects, which are also observed in healthy subjects, are severely limited by tachyphylaxis and are not clinically significant.18,20,21,30–32 Thus, although nicotine itself has no useful therapeutic effect, its actions prompt investigation of less toxic and more effective agonists.

DMXB-A is a derivative of the naturally occurring alkaloid anabaseine.27 DMXB-A is a partial agonist at human {alpha}7-nicotinic receptors and at higher concentrations a weak {alpha}4ß2 receptor and serotonin 5-HT3 receptor antagonist.27,28,33,34 The partial agonist activity of DMXB-A may help to minimize the problem of tachyphylaxis observed with the full agonist nicotine. DMXB-A had a positive effect on neurocognition in an initial single-dose proof of concept test in 12 people with schizophrenia.35 The subjects were concurrently treated with antipsychotic drugs and were currently nonsmoking. Subjects who smoked were excluded to prevent interference with effects of DMXB-A by the effects of chronic exposure to nicotine. The effects for some subjects were sufficiently robust, ie, an 8- to 12-point increase in Repeatable Battery for the Assessment of Neuropsychological Status total scale score,36 to be suggestive of a meaningful clinical effect. There was an accompanying increase in the suppression of the P50 auditory evoked potential to repeated stimuli. Increased inhibition of the P50 response during DMXB-A supports the hypothesis of an agonist effect on {alpha}7-receptors located on inhibitory interneurons. In animal models, stimulation of {alpha}7-nicotinic receptors with DMXB-A selectively decreases the test response amplitude, as was found in this study.37 The study results suggest that inhibitory circuits, which are normally responsible for suppression of the test response and appear to be dysfunctional in schizophrenia, may remain susceptible to activation by nicotinic agonists, as well as other treatments.

Several compounds in current clinical use may also have direct or indirect effects on {alpha}7-nicotinic receptors. Galantamine is discussed below. Tropisetron, a 5HT3 antagonist approved for use outside the United States as an antinausea drug, has nearly equal potency as an {alpha}7-nicotinic receptor agonist. Tropisetron also improves the inhibition of P50 responses in schizophrenia, perhaps through {alpha}7-nicotinic receptor agonism.38 The SGA clozapine is not a direct nicotinic agonist, but it indirectly increases release of acetylcholine in the hippocampus, a property not shared by FGAs and other SGAs.39 Clozapine increases P50 auditory response inhibition in schizophrenia, with animal models demonstrating that this effect is mediated by stimulation of {alpha}7-nicotinic receptors.40,41 Clinical response to clozapine is greater in people with schizophrenia who smoke before the initiation of treatment, compared with those who do not, and also results in decreased smoking behavior during treatment, perhaps consistent with nicotinic cholinergic agonism as 1 mechanism of its antipsychotic effect.42,43

Acetylcholinesterase Inhibitor Agents
Acetylcholinesterase inhibitors (AChEIs) act primarily through the inhibition of acetylcholinesterase, the enzyme primarily responsible for metabolizing acetylcholine in the synaptic cleft and terminating cholinergic transmission. Inhibition of the enzyme increases the amount of acetylcholine at both the muscarinic and nicotinic cholinergic receptors.

There have been a series of studies of AChEIs in schizophrenia.44 The most frequently tested agent has been donepezil. Although several open-label and small sample–controlled studies have suggested a beneficial effect on cognitive impairments,45–47 large controlled trials have failed to demonstrate a beneficial effect on cognition48–51. In the largest study to date (121 subjects randomized to donepezil and 124 subjects randomized to placebo), donepezil did not differ from placebo on the global composite score or on any of the individual cognitive measures.51 Similarly, positive open-label reports of a beneficial effect of rivastigamine,52,53 have not been replicated in a double-blind, placebo-controlled study.54 There have been 2 published double-blind, placebo-controlled galantamine studies55,56 and 2 unpublished studies (http://clinicaltrials.gov; Buchanan et al57). In the small-sample size, double-blind, placebo-controlled studies (n = 14; 55, n = 24; 56), galantamine treatment was associated with selective benefits for attention and delayed memory55,56 and visual recognition.56 In a larger double-blind, placebo-controlled study (n = 73), Buchanan et al57 failed to find a significant galantamine/placebo difference for the global composite score. However, galantamine did exert a significant benefit for processing speed and verbal memory. Finally, in an industry-sponsored study, there was no significant difference between galantamine and placebo on a global measure of cognition (http://clinicaltrials.gov). The results for individual measures were not provided.

In general, the AChEI results have not been overly supportive of this approach. There is a suggestion that galantamine, in contrast to donepezil and rivastigmine, may have selected benefits for verbal memory and processing speed measures.55–57 If the galantamine results are valid, then the question arises, why does galantamine have a beneficial effect for cognition but donepezil and rivastigmine apparently do not? One possible explanation is that, in addition to its AChEI actions, galantamine is also a positive allosteric modulator of the {alpha}4ß2 and {alpha}7-nicotinic receptors.58–61 The allosteric properties of galantamine could directly lead to increased release of acetylcholine and sensitization of postsynaptic nicotinic receptors59 or indirectly effect cognition through its effects on the release of other neurotransmitters, especially glutamate and DA.61,62 Schilström et al61 have recently demonstrated that galantamine increases dopaminergic activity and release in the prefrontal cortex in a dose-dependent manner. Wang et al62 demonstrated that galantamine increased DA release in the hippocampus, through its allosteric mechanism, and that this effect of galantamine was related to its ability to improve cognitive impairments in a mouse model of Alzheimer disease.

Summary
There is an extensive literature supporting the beneficial effects of acute nicotine administration on cognitive impairments in people with schizophrenia. Whether this effect is mediated through the {alpha}4ß2 or {alpha}7 or both nicotinic receptors has not been clearly established. The advent of selective agents for these receptors will enable the eventual delineation of their respective therapeutic roles. Initial studies with DMXB-A and galantamine suggest that agents that act as either partial agonists or allosteric modulators of the {alpha}4ß2 or {alpha}7-nicotinic receptors may be of particular interest.


   Dopaminergic Agents
Top
 Abstract
 Introduction
 Cholinergic Agents
 Dopaminergic Agents
Glutamate
 Conclusion
 References
 
Introduction
The DA system has long been integral to our understanding of the pathphyisology of schizophrenia.63–66 Although, historically, DA was thought to be involved in positive symptom pathophysiology, more recently, it has also been implicated in the pathophysiology of negative symptoms and cognitive impairments.65,67–69 Specifically, it has been hypothesized that schizophrenia involves a biphasic dysregulation of DA signaling, in which subcortical mesolimbic DA pathways are disinhibited and overactive and mesocortical DA pathways are underactive; the combination of these effects results in decreased prefrontal DA signaling.70,71 This model is consistent with the pattern of cognitive impairments seen in schizophrenia, which includes functions mediated by frontal cortical structures such as working memory and executive functions.72 The model is also consistent with functional brain imaging studies in which people with schizophrenia demonstrated abnormal prefrontal activation associated with impaired performance of cognitive tasks (eg, working memory, executive functions).73,74

Although this model has been heuristic, it has presented significant challenges for the development of therapeutic agents. The use of DA antagonists to suppress overactivity, while therapeutic for positive symptoms, runs the risk of exacerbating negative symptoms and cognitive impairments by further decreasing DA signaling in the frontal cortex. At the same time, the use of indirect DA agonists, while proven to be effective in transiently reducing negative symptoms and improving cognition, risks exacerbating psychosis.75,76 Thus, more precise pharmacodynamic approaches are needed.

D1 Agonists
DA signaling is mediated by DA receptor subtypes that are members of the G protein–coupled receptor superfamily.77–79 The receptors are categorized into 2 groups, D1 like and D2 like. D2 receptors are predominantly expressed in subcortical regions including the midbrain, corpus striatum, and pituitary. A number of direct agonists are available clinically that target the D2-like family of receptors. However, the development of clinically viable D1 full agonists has proven to be a challenge. The D1-like receptors (D1 or D1A and D5 or D5B) are prominent in the brain cortical regions that are intimately associated with executive, cognitive, and motor functions such as the prefrontal cortex. The majority of prefrontal DA receptors are of the D1 subtype80,81 and display a bilaminar distribution (high in layers I, II, IIIa, V, and Vi; low in IIIb and IV).82,83 Pharmacological, electrophysiological, and anatomical evidence suggest that D1 receptors are critical mediators of the direct and indirect modulatory effect of DA on pyramidal cell activity.84,85 Prior studies (postmortem and in vivo neuroimaging) suggest that D1 receptors may be upregulated in schizophrenia86–89; an effect presumably due to a chronic impairment in DA tone in the cortex.

The location and function of D1 receptors make them attractive targets for the treatment of negative symptoms and cognitive impairments. Although support for this strategy comes from the work of many investigators, the work of the late Patricia Goldman-Rakic was particularly influential.90,91 Preclinical studies from her laboratory showed that chronic blockade of DA D2 receptors by antipsychotic drugs down regulates D1 receptors in the prefrontal cortex and produces severe impairments in working memory. More specifically, studies in primates showed that the D1 agonist ABT-431 reversed working memory deficits associated with chronic antipsychotic therapy.92,93 Consequently, there is a strong rationale for evaluating the potential efficacy of DA D1 agonists in people with schizophrenia. The most promising compounds are DAR-0100 and its stereoisomer DAR-0100A.

DAR-0100 (published as dihydrexidine; ([±]-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo [a]phenanthridine; see Table 1) is a potent, full-efficacy D1 DA receptor agonist.94–96 DAR-0100 binds with high affinity to the D1 receptor (IC50 = 10 nM). Additionally, DAR-0100 has been screened for activity at 40 additional binding sites and found to be inactive (IC50 > 10 uM) at all except D2 DA receptors (IC50 = 130 nM) and {alpha}2 adrenergic receptors (IC50 = 230 nM).97 DAR-0100 is as efficacious as DA and approximately 70 times more potent in the stimulation of adenylate cyclase.94–96 This effect is blocked by the Dl antagonist SCH 23390 but not by D2, 5-HT2, muscarinic, or alpha- or beta-adrenergic receptor antagonists.96 Despite its D2 affinity, the functional effects of DAR-0100, both in situ and in vivo, are attributable almost entirely to interaction with the D1 receptor.98–101 Binding and functional activity are associated only with the dextrorotatory enantiomer, DAR-0100A.102


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  		Table 1. Binding Affinities of DAR-0100 at Striatal D1 and D2 Receptors

 
While many have recognized the value of a full D1 agonist in the treatment of a variety of neurological and psychiatric disorders, the advancement of this type of drug has been hindered by a variety of factors. In the case of DAR-0100, the issues preventing the advancement to market had been (1) a lack of oral bioavailability, and (2) a short half-life that would require repeated daily dosing. With the patch or pump delivery devices now available for subcutaneous administration, as well as buccal administrations such as Zydis, these limited hindrances can be resolved. Compounds such as DAR-0100 can be formulated into viable treatment options, allowing the drug to be practically administered. The low dosing level required would limit the potential for hypotension, an unintended effect related to peripheral D1 receptors, seen with all DA agonists.

To date, DAR-0100 has been tested as a single 20-mg dose (15-minute subcutaneous infusion) in 4 people with Parkinson disease103 and 20 people with schizophrenia104 with no significant blood pressure drop. In the latter study, the effects of DAR-0100 on the neural correlates of working memory (BOLD signal) were recently investigated using a 3T MRI scanner during a 2-back working memory task. Gadolinium perfusion sequences prior to and after DAR-0100 were also acquired.

Summary
Although there is extensive data to support the utility of the D1 agonist strategy, practical issues have hindered the development of drugs to adequately evaluate this approach. However, if successful, then this approach would constitute yet another practical benefit from the durable DA hypothesis of schizophrenia.


   Glutamate
Top
 Abstract
 Introduction
 Cholinergic Agents
 Dopaminergic Agents
 Glutamate
Conclusion
 References
 
Introduction
Glutamate is the primary excitatory neurotransmitter in brain. It is contained as a neurotransmitter in approximately 60% of brain neurons, including almost all cortical pyramidal neurons. Further, virtually 100% of brain neurons contain some type of glutamate receptor. The role of glutamate as a transmitter was only discovered only about 25 years ago.105 To date, few medications are available that impact meaningfully on glutamatergic neurotransmission. Nevertheless, the last decade has seen a dramatic increase in interest in the glutamatergic system on the part of major pharmaceutical companies and a growing number of compounds targeting glutamate entering preclinical and clinical testing.

Glutamate mediates its CNS effects via both ionotropic and metabotropic receptors. Ionotropic receptors are differentiated based upon sensitivity to the synthetic glutamate derivatives N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. NMDA receptors are particularly linked to schizophrenia based upon the psychotomimetic actions of NMDA antagonists including phencyclidine and ketamine.106

Metabotropic receptors are divided into several groups, which show differential effects on glutamatergic function. Group I receptors, consisting of mGluR1 and mGluR5, function predominantly to potentiate both presynaptic glutamate release and postsynaptic NMDA neurotransmission. Conversely, group II (mGluRs 2 and 3) and Group III (mGluRs 4, 6, 7, and 8) receptors serve to limit glutamate release, particularly during conditions of glutamate spillover from the synaptic cleft.

In general, based upon the action of NMDA antagonists, it is posited that schizophrenia is associated with reduced glutamatergic neurotransmission. Treatment strategies, therefore, have attempted to potentiate glutamatergic neurotransmission at either NMDA or non-NMDA receptors. It has also been proposed, however, that some symptoms of schizophrenia result from rebound hyperglutamatergia secondary to primary NMDA blockade. Such deficits may be reversed, particularly in frontal areas, by mGluR group II/III agonists, which may also reverse effects of ketamine in both rodent107 and human108 studies.

Specific Targets
There are 3 major classes of glutamatergic targets: NMDA, AMPA, and metabotropic receptors.

NMDA Receptors: Glycine Site Agents. NMDA receptors contain multiple binding sites, which may serve as targets for drug development. Target development to date has focused primarily on the glycine allosteric modulatory site. Proof of concept studies have been conducted using naturally occurring agonists of the glycine receptor as medical treatments. In general, the full agonists, such as glycine, have proven more effective than the partial agonist D-cycloserine.109,110 Further, effects have generally been more robust when these agents have been used in combination with antipsychotics other than clozapine, suggesting that clozapine's unique therapeutic effects may be due, in part, to its ability to stimulate NMDA receptor–mediated neurotransmission.111

To date, 7 small-scale studies have been published in which full agonists were combined with FGAs or SGAs other than clozapine. In these studies, glycine has been used at doses of 0.4–0.8 g/kg (approximately 30–60 g/d),112–115 D-serine at doses of 30 mg/kg (approximately. 2.1 g/d),116,117 and D-alanine at a dose of 100 mg/kg (approximately. 7 g/d).118 These studies have involved a total of approximately 200 subjects. Across all studies, a highly significant (P < .0001), roughly 20% improvement in negative symptoms was observed, along with improvement in the Positive and Negative Syndrome Scale (PANSS) "cognitive" symptom cluster. The PANSS "cognitive" symptom is comprised of symptoms, such as poor attention and disorientation, thought to be related to cognitive function, and is not a formal assessment of cognitive function.

Only 2 studies to date have reported neuropsychological test results.115,119 In the first study, there was a significant D-serine/placebo group difference in Wisconsin Card Sort Test categories completed, but perseverative error rate was not differentially affected. A large multicenter study of glycine (n = 37) versus D-cycloserine (n = 41) versus placebo (n = 37) did not find either cognitive improvement, as assessed using a MATRICS-like neuropsychological test battery, or overall therapeutic effectiveness of either glycine or D-cycloserine, leaving unresolved whether cognitive improvement would occur in the context of significant symptomatic change.119

Because of the involvement of NMDA receptors in neurodevelopment, neuroplasticity, and trophic brain functions, an ideal use of the compounds may be in reversing symptoms and neurocognitive symptoms early in the schizophrenia prodrome, prior to any long-term, irreversible structural changes. One small-scale, (n = 10) open-label study of glycine in prodromal schizophrenia found large (d = 1.2) effect-size changes on prodromal symptoms,120 which were larger than those observed in a prior double-blind trial of olanzapine. However, double-blind findings with NMDA agonists in the schizophrenia prodrome are not yet available. In this study as well, no cognitive endpoints were included.

NMDA Receptors: Glycine Transport Inhibitors. A second approach to treatment has been use of glycine transport inhibitors (GTIs) to increase extracellular glycine levels by preventing neuronal and glial uptake. Although clinical data with GTIs remain limited, 2 small-scale studies have been performed with the naturally occurring compound sarcosine, given at a dose of approximately 2 g/d. In 1 study, sarcosine treatment produced a 17% reduction in PANSS negative symptoms, a 14% reduction in PANSS positive symptoms, and a 13% improvement in PANSS "cognitive" symptom cluster in people with chronic schizophrenia stabilized on FGAs or SGAs.121 More recently, similar effects were observed following addition of sarcosine to risperidone treatment for acutely decompensated subjects.122 As with direct glycine site agonists, no beneficial effects of sarcosine were observed in clozapine-treated people with schizophrenia.123

Lead GLYT1 inhibitors currently entering clinical testing show approximately 1000-fold greater potency than sarcosine at the GLYT1 transporters, along with >1000-fold selectivity versus other CNS targets. Encouraging preclinical results have been observed with several prototypic GTIs, including glycyldodecylamide,124 N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS),125–128 Org24461,128 Org 24598,129 and SSR504734,130 in several preclinical assays thought to be relevant to neurocognition, including potentiation of NMDA receptor activity in vitro and in vivo, and reversal of schizophrenia-like prepulse inhibition abnormalities124,128,130–136 (Table 2). Nevertheless, clinical data remain lacking.


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  		Table 2. Preclinical Paradigms of Relevance to Schizophrenia in Which Glycine Transport Inhibitors Have Been Shown to Potential Beneficial Effects

 

AMPA Receptors. AMPA receptors mediate the bulk of fast glutamatergic neurotransmission in the brain. In addition, AMPA receptors work synergistically with NMDA receptors and are needed to maintain overall integrity of glutamate synapses. AMPA receptors desensitize quickly following agonist stimulation at the AMPA glutamate receptor site, which limits the utility of this approach. However, allosteric modulators, termed AMPAkines, may be able to stimulate AMPA receptors without causing desensitization. AMPAkines have been found to improve cognitive performance in animal models137,138 and to act synergistically with antipsychotics to reverse amphetamine-induced hyperactivity.139 To date, 2 clinical studies have been published with the AMPAkine CX-516. In a small n study (n = 19) of CX-516 added to clozapine, improvements in memory and attention were observed despite lack of symptomatic improvement.140 However, in a larger multicenter study (n = 95), CX-516 was not found to be effective when added to clozapine, olanzapine, or risperidone.141 CX-516 has also been studied as monotherapy, with no clear beneficial effects.142 Studies of other, high-affinity, more potent AMPAkines are ongoing, which may provide a more rigorous test of the utility of this approach.

Metabotropic Receptors. As opposed to ionotropic receptors, which are linked directly to ion channels, metabotropic receptors are linked to second messenger systems and affect neuronal metabolism, leading to alterations in glutamate release. Metabotropic receptors are divided into 3 groups based upon functional activity and structure.143 One agent in particular, LY354740, a group II agonist, has been found to reverse effects of NMDA antagonists in both rodents and humans,107,108 suggesting a potential role in treatment of schizophrenia. Recently, encouraging phase II results have been reported for the mGlu2/3 agonist LY2140023144 (http://www.lillytrials.com/initiated/studies/initiated_9777.html), especially against positive symptoms. However, no neuropsychological battery was included in the study; thus, the effects of these agents on neurocognition remain lacking.

Summary
Glutamatergic function remains an area of active drug development, with promising preclinical results having been reported for several classes of compound. Many compounds are only now entering early-stage clinical trials. Because of the NMDA effects on brain development and neuroplasticity, glutamatergic agents may be particularly appropriate for reversal of symptoms and emerging neurocognitive dysfunction in prodromal schizophrenia, although double-blind, randomized controlled clinical trials are required.


   Conclusion
Top
 Abstract
 Introduction
 Cholinergic Agents
 Dopaminergic Agents
 Glutamate
 Conclusion
References
 
The MATRICS and TURNS project mechanisms have stimulated considerable interest in the development of cognitive-enhancing agents. Multiple cholinergic, dopaminergic, and glutamatergic agents have been developed and are in the early stages of evaluation. Preliminary results with agents that modulate the {alpha}4ß2 or {alpha}7-nicotinic receptors are supportive of this approach. For various reasons, the development of dopaminergic and glutamatergic agents has lagged behind that of cholinergic agents and there is less clinical data to support these approaches, though the theoretical rationale for both is very strong. Despite these efforts, cognitive impairments remain one of the most important unmet therapeutic challenges in schizophrenia. The ultimate tribute to Wayne Fenton will be the successful development of an effective drug for this indication.


  Footnotes
 
1 To whom correspondence should be addressed; tel: 410-402-7876; fax: 410-402-7198; e-mail: rwbuchanan{at}mprc.umaryland.edu.


   Acknowledgments
 
Dr Javitt holds intellectual property rights for use of glycine-site agonist and glycine transport inhibitors for treatment of schizophrenia and holds stock in Glytech, a company developing these compounds for clinical use.


   References
Top
 Abstract
 Introduction
 Cholinergic Agents
 Dopaminergic Agents
 Glutamate
 Conclusion
 References
 

  1. Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res (2004) 72::29–39.[CrossRef][Web of Science][Medline]

  2. Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry (2004) 55::1013–1022.[CrossRef][Web of Science][Medline]

  3. Woodward ND, Purdon SE, Meltzer HY, Zaid DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol (2005) 8::457–472.[CrossRef][Web of Science][Medline]

  4. Keefe RSE, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry (2007) 64::633–647.[Abstract/Free Full Text]

  5. Geyer M, Tamminga CA. Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects. Psychopharmacology (Berl) (2004) 174::1–2.

  6. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry (2000) 157::4–15.[Abstract/Free Full Text]

  7. Broocks A, Little JT, Mrtin A, et al. The influence of ondasetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls. Biol Psychiatry (1998) 43::408–416.[CrossRef][Web of Science][Medline]

  8. Furey ML, Pietrini P, Haxby JV. Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science (2000) 290::2315–2319.[Abstract/Free Full Text]

  9. Vitiello B, Martin A, Hill J, et al. Cognitive and behavioral effects of cholinergic, dopaminergic, and serotonergic blockade in humans. Neuropharmacology (1997) 16::15–24.

  10. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry (2000) 48::381–388.[CrossRef][Web of Science][Medline]

  11. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry (2001) 158::918–925.[Abstract/Free Full Text]

  12. Deng C, Huang XF. Decreased density of muscarinic receptors in the superior temporal gyrus in schizophrenia. J Neurosci Res (2005) 81::883–890.[CrossRef][Web of Science][Medline]

  13. Freedman R, Hall M, Adler LE, Leonard S. Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry (1995) 38::22–33.[CrossRef][Web of Science][Medline]

  14. Guan ZZ, Zhang X, Blennow K, Nordberg A. Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport (1999) 10::1779–1782.[Web of Science][Medline]

  15. Breese CR, Lee MJ, Adams CE, et al. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology (2000) 23::351–364.[CrossRef][Web of Science][Medline]

  16. Raedler TJ, Knable MB, Jones DW, et al. In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry (2003) 160::118–127.[Abstract/Free Full Text]

  17. Adler LE, Olincy A, Waldo M, et al. Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull (1998) 24::189–202.[Abstract/Free Full Text]

  18. Depatie L, O'Driscoll G, Holahan A-L, et al. Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study. Neuropsychopharmacology (2002) 27::1056–1070.[CrossRef][Web of Science][Medline]

  19. Avila MT, Sherr JD, Hong E, Myers CS, Thaker GK. Effects of nicotine on leading saccades during smooth pursuit eye movements in smokers and nonsmokers with schizophrenia. Neuropsychopharmacology (2003) 28::2184–2191.[Web of Science][Medline]

  20. Harris JG, Kongs S, Allensworth DA, Sullivan B, Zerbe G, Freedman R. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology (2004) 29::1378–1385.[CrossRef][Web of Science][Medline]

  21. Myers CS, Robles O, Kakoyannis AN, et al. Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology (Berl) (2004) 174::334–340.[Medline]

  22. Sacco KA, Termine A, Seyal A, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry (2005) 62::649–659.[Abstract/Free Full Text]

  23. Baldeweg T, Wong D, Stephan KE. Nicotinic modulation of human auditory sensory memory: evidence from mismatch negativity potentials. Int J Psychophysiol (2006) 59::49–58.[CrossRef][Medline]

  24. George TP, Termine A, Sacco KA, et al. A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms. Schizophr Res (2006) 87::307–315.[CrossRef][Web of Science][Medline]

  25. Smith RC, Warner-Cohen J, Matute M, et al. Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology (2006) 31::637–643.[CrossRef][Web of Science][Medline]

  26. Walker DP, Wishka DG, Piotrowski DW, et al. Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists. Bioorg Med Chem (2006) 14::8219–8248.[CrossRef][Medline]

  27. Kem WR, Mahnir VM, Prokai L, et al. Hydroxy metabolites of the Alzheimer's drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21): their molecular properties, interactions with brain nicotinic receptors, and brain penetration. Mol Pharmacology (2004) 65::56–67.[Abstract/Free Full Text]

  28. De Fiebre CM, Meyer EM, Henry JC, Muraskin SI, Kem WR, Papke RL. Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha-7/125 I-alpha-bungarotoxin receptor subtypes. Mol Pharmacology (1995) 47::164–171.[Abstract]

  29. Olincy A, Young DA, Freedman R. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry (1997) 42::1–5.[CrossRef][Web of Science][Medline]

  30. Jacobsen LK, D'Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH. Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry (2004) 55::850–858.[CrossRef][Web of Science][Medline]

  31. Smith RC, Singh A, Infante M, Khandat A, Kloos A. Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology (2002) 27::479–497.[CrossRef][Web of Science][Medline]

  32. George T, Vessicchio J, Termine A, et al. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology (2002) 26::75–85.[CrossRef][Web of Science][Medline]

  33. Briggs CA, McKenna DG, Piattoni-Kaplan M. Human alpha-7 nicotinic acetylcholine receptor responses to novel ligands. Neuropharmacology (1995) 34::583–590.[CrossRef][Web of Science][Medline]

  34. Stokes C, Papke JK, Horenstein NA, Kem WR, McCormack TJ, Papke RL. The structural basis for GTS-21 selectivity between human and rat nicotinic alpha7 receptors. Mol Pharmacology (2004) 66::14–24.[Abstract/Free Full Text]

  35. Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an {alpha}7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry (2006) 63::630–638.[Abstract/Free Full Text]

  36. Gold JM, Queern C, Iannone VN, Buchanan RW. Repeatable battery for the assessment of neuropsychological status as a screening test in schizophrenia I: sensitivity, reliability, and validity. Am J Psychiatry (1999) 156::1944–1950.[Abstract/Free Full Text]

  37. Stevens KE, Kem WR, Mahnir VM, Freedman R. Selective alpha-7 nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl) (1998) 136::320–327.[CrossRef][Medline]

  38. Koike K, Hashimoto K, Takai N, et al. Tropisetron improves deficits in auditory sensory P50 suppression in schizophrenic patients. Schizophr Res (2005) 76::67–72.[CrossRef][Web of Science][Medline]

  39. Chung YC, Li Z, Dai J, Meltzer HY, Ichikawa J. Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res (2004) 1023::54–63.[CrossRef][Web of Science][Medline]

  40. Adler LE, Olincy A, Cawthra E, et al. The varied effects of atypical medications on P50 auditory gating in schizophrenic patients. Am J Psychiatry (2004) 161::1822–1828.[Abstract/Free Full Text]

  41. Simosky JK, Stevens KE, Adler LE, Freedman R. Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) (2003) 165::386–396.[Medline]

  42. George TP, Serynak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry (1997) 56::344–346.

  43. McEvoy JP, Freudenreich O, Wilson W. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry (1999) 46::125–129.[CrossRef][Web of Science][Medline]

  44. Ferreri F, Agbokou C, Gautheir S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci (2006) 31::369–376.[Web of Science][Medline]

  45. Buchanan RW, Summerfelt A, Tek C, Gold J. An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. Schizophr Res (2003) 59::29–33.[CrossRef][Web of Science][Medline]

  46. Stryjer R, Strous RD, Bar F, et al. Donepezil augmentation of clozapine monotherapy in schizophrenia patients: A double blind cross-over study. Hum Psychopharmacol (2004) 19::343–346.[CrossRef][Web of Science][Medline]

  47. Erickson SK, Schwarzkopf SB, Palumbo D, Badgley-Fleeman J, Smirnov AM, Light GA. Efficacy and tolerability of low-dose donepezil in schizophrenia. Clin Neuropharmacol (2005) 28::179–184.[CrossRef][Web of Science][Medline]

  48. Friedman JI, Adler DN, Howanitz E, et al. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry (2002) 51::349–357.[CrossRef][Web of Science][Medline]

  49. Freudenreich O, Herz L, Deckersbach T, et al. Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) (2005) 181::358–363.[CrossRef][Medline]

  50. Fagerlund B, Soholm B, Fink-Jensen A, Lublin H, Glenthoj BY. Effects of donepezil adjunctive treatment of ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study. Clin Neuropharmacol (2007) 30::3–12.[CrossRef][Web of Science][Medline]

  51. Keefe RSE, Malhotra AK, Meltzer H, Kane JM, Buchanan RW, Murthy A, Sovel M, Li C, Goldman R. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo effects in a 12-week, randomized, double-blind, placebo-controlled trial. Clin Neuropsychopharmacology . In press.

  52. Lenzi A, Maltinti E, Poggi E, Fabrizio L, Coli E. Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. Clin Neuropharmacol (2003) 26::317–321.[CrossRef][Web of Science][Medline]

  53. Mendelsohn E, Rosenthal M, Bohiri Y, Werber E, Kotler M, Strous RD. Rivastigmine augmentation in the management of chronic schizophrenia with comorbid dementia: an open-label study investigating effects on cognition, behaviour and activities of daily living. Int Clin Psychopharmacol (2004) 19::319–324.[CrossRef][Web of Science][Medline]

  54. Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophr Res (2006) 85::73–83.[CrossRef][Web of Science][Medline]

  55. Schubert MX, Young KA, Hicks PB. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry (2006) 60::530–533.[CrossRef][Web of Science][Medline]

  56. Lee S-W, Lee J-G, Lee B-J, Kim YH. A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharmacol (2007) 22::63–68.[CrossRef][Web of Science][Medline]

  57. Buchanan RW, Conley RR, Dickinson D, Nelson MW, Gold JM, McMahon RP. Galantamine for the treatment of cognitive impairments in patients with schizophrenia. Schizophr Bull (2007) 33::424.

  58. Maelicke A, Albuquerque EX. Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease. Eur J Pharmacol (2000) 393::165–170.[CrossRef][Web of Science][Medline]

  59. Samochocki M, Höffle A, Fehrenbacher A, et al. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmcol Exp Ther (2003) 305::1024–1036.[Abstract/Free Full Text]

  60. Dajas-Bailador FA, Heimala K, Wonnacott S. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol (2003) 64::1217–1226.[Abstract/Free Full Text]

  61. Schilström B, Ivanov VB, Wiker C, Svensson TH. Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology (2007) 32::43–53.[CrossRef][Web of Science][Medline]

  62. Wang D, Noda Y, Zhou Y, et al. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 I.c.v.-injected mice: involvement of dopaminergic systems. Neuropsychopharmacology (2006) 1–11.

  63. Meltzer HY, Stahl SM. The dopamine hypothesis of schizophrenia: a review. Schizophr Bull (1976) 2::19–76.[Free Full Text]

  64. Carlsson A. Does dopamine play a role in schizophrenia? Psychol Med (1977) 7::583–597.[Web of Science][Medline]

  65. Crow TJ. Positive and negative schizophrenia symptoms and the role of dopamine. Br J Psychiatry (1981) 139::251.[Free Full Text]

  66. Seeman P, Bzowej NH, Guan HC, et al. Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Hunington's diseases. Neuropsychopharmacology (1987) 1::5–15.[CrossRef][Web of Science][Medline]

  67. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry (1987) 44::660–669.[Abstract/Free Full Text]

  68. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry (1991) 148::1474–1486.[Abstract/Free Full Text]

  69. Carlsson ML, Carlsson A, Nilsson M. Schizophrenia: from dopamine to glutamate and back. Curr Med Chem (2004) 11::267–277.[CrossRef][Web of Science][Medline]

  70. Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature (1980) 286::74–77.[CrossRef][Medline]

  71. Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull (1990) 16::425–432.[Abstract/Free Full Text]

  72. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry (1996) 153::321–330.[Abstract/Free Full Text]

  73. Goldberg TE, Patterson KJ, Taqqu Y, Wilder K. Capacity limitations in short-term memory in schizophrenia: tests of competing hypotheses. Psychol Med (1998) 28::665–673.[CrossRef][Web of Science][Medline]

  74. Barch DM, Sheline YI, Csernansky JG, Snyder AZ. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol Psychiatry (2003) 53::376–384.[CrossRef][Web of Science][Medline]

  75. Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) (1987) 91::415–433.[CrossRef][Medline]

  76. Jaskiw GE, Popli AP. A meta-analysis of the response to chronic L-dopa in patients with schizophrenia: therapeutic and heuristic implications. Psychopharmacology (Berl) (2004) 171::365–374.[CrossRef][Medline]

  77. Neve KA, Neve RL. The Dopamine Receptors (1997) Totowa, NJ: Humana Press.

  78. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev (1998) 78::189.[Abstract/Free Full Text]

  79. Huang X, Lawler CP, Lewis MM, Nichols DE, Mailman RB. D1 dopamine receptors. Int Rev Neurobiol (2001) 48::65.[Web of Science][Medline]

  80. De Keyser J, Ebinger G, Vauquelin G. Evidence for a widespread dopaminergic innervation of the human cerebral neocortex. Neurosci Lett (1989) 104::281–285.[CrossRef][Web of Science][Medline]

  81. Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L. Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology (1994) 11::245–256.[Web of Science][Medline]

  82. Dawson TM, McCabe RT, Stensaas SS, Wamsley JK. Autoradiographic evidence of [3H]SCH23390 binding sites in human prefrontal cortex (Brodmann's area 9). J Neurochem (1987) 49::789–796.[Web of Science][Medline]

  83. Lidow MS, Goldman-Rakic PS, Rakic P, Gallager DW. Autoradiographic comparison of D1-specific binding of [3H]SCH39166 and [3H]SCH23390 in the primate cerebral cortex. Brain Res (1990) 537::349–354.[CrossRef][Web of Science][Medline]

  84. Yang CR, Seamans JK. Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration. J Neurosci (1996) 16::1922–1935.[Abstract/Free Full Text]

  85. Seamans JK, Gorelova N, Durstewitz D, Yang CR. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci (2001) 21::3628–3638.[Abstract/Free Full Text]

  86. Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol (1997) 11::123–131.[Abstract/Free Full Text]

  87. Akil M, Pierri JN, Whitehead RE, et al. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry (1999) 156::1580–1589.[Abstract/Free Full Text]

  88. Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev (2000) 31::295–301.[CrossRef][Medline]

  89. Abi-Dargham A, Mawlawi O, Lombardo I, et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci (2002) 22::3708–3719.[Abstract/Free Full Text]

  90. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) (1994) 116::143–151.[CrossRef][Medline]

  91. Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science (1991) 251::947–950.[Abstract/Free Full Text]

  92. Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science (2000) 287::2020–2022.[Abstract/Free Full Text]

  93. Castner SA, Goldman-Rakic PS. Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J Neurosci (2004) 24::1446–1450.[Abstract/Free Full Text]

  94. Lovenberg TW, Brewster WK, Mottola DM, et al. Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist. Eur J Pharmacol (1989) 166::111–113.[CrossRef][Web of Science][Medline]

  95. Brewster WK, Nichols DE, Riggs RM, et al. trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist. J Med Chem (1990) 33::1756–1764.[CrossRef][Web of Science][Medline]

  96. Mottola DM, Brewster WK, Cook LL, NIchols DE, Mailman RB. Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. J Pharmacol Exp Ther (1992) 262::383–393.[Abstract/Free Full Text]

  97. Mottola DM, Laiter S, Watts VJ, et al. Conformational analysis of D1 dopamine receptor agonists: pharmacophore assessment and receptor mapping. J Med Chem (1996) 39::285–296.[CrossRef][Web of Science][Medline]

  98. Darney KJ Jr, Lewis MH, Brewster WK, Nichols DE, Mailman RB. Behavioral effects in the rat of dihydrexidine, a high-potency, full-efficacy D1 dopamine receptor agonist. Neuropsychopharmacology (1991) 5::187–195.[Web of Science][Medline]

  99. Kohli JD, Horn PT, Glock D, Brewster WK, Nichols DE. Dihydrexidine: a new potent peripheral dopamine D1 receptor agonist. Eur J Pharmacol (1993) 235::31–35.[CrossRef][Web of Science][Medline]

  100. Mottola DM, Kilts JD, Lewis MM, et al. Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase. J Pharmacol Exp Ther (2002) 301::1166–1178.[Abstract/Free Full Text]

  101. Kilts JD, Connery HS, Arrington EG, et al. Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs. J Pharmacol Exp Ther (2002) 301::1179–1189.[Abstract/Free Full Text]

  102. Knoerzer TA, Nichols DE, Brewster WK, Watts VJ, Mottola D, Mailman RB. Dopaminergic benzo[a]phenanthridines: resolution and pharmacological evaluation of the enantiomers of dihydrexidine, the full efficacy D1 dopamine receptor agonist. J Med Chem (1994) 37::2453–2460.[CrossRef][Web of Science][Medline]

  103. Blanchet PJ, Fang J, Gillespie M, et al. Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkin's disease. Clin Neuropharmacol (1998) 21::339–343.[Web of Science][Medline]

  104. George MS, Molnar CE, Grenesko EL, et al. A single 20mg dose of dihydrexidine (DAR-0100), a full dopamine D (1) agonist, is safe and tolerated in patients with schizophrenia. Schizophr Res (2007) 93::42–50.[CrossRef][Medline]

  105. Cotman CW, Monaghan DT. Chemistry and anatomy of excitatory amino acid systems. In: Psychopharmacology: The Third Generation of Progress —Meltzer HY, ed. (1987) New York, NY: Raven Press. 197–210.

  106. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry (1991) 148::1301–1308.[Abstract/Free Full Text]

  107. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science (1998) 281::1349–1352.[Abstract/Free Full Text]

  108. Krystal JH, Abi-Saab W, Perry E, et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) (2004) 179::303–309.

  109. Goff DC, Herz L, Posever T, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) (2005) 179::144–150.[CrossRef][Medline]

  110. Heresco-Levy U, Javitt DC. Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res (2004) 66::89–96.[CrossRef][Web of Science][Medline]

  111. Javitt DC, Duncan L, Balla A, Sershen H. Inhibition of system A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action. Mol Psychiatry (2005) 10::275–287.[CrossRef][Medline]

  112. Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP. Amelioration of negative symptoms in schizophrenia by glycine. Am. J Psychiatry (1994) 151::1234–1236.[Abstract/Free Full Text]

  113. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry (1999) 56::29–36.[Abstract/Free Full Text]

  114. Javitt DC, Silipo G, Cienfuegos A, et al. Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol (2001) 4::385–392.[Web of Science][Medline]

  115. Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry (2004) 55::165–171.[CrossRef][Web of Science][Medline]

  116. Tsai G, Yang P, Chung LC, Lange N, Coyle JT. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry (1998) 44::1081–1089.[CrossRef][Web of Science][Medline]

  117. Heresco-Levy U, Javitt DC, Ebstein R, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry (2005) 57::577–585.[CrossRef][Web of Science][Medline]

  118. Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry (2006) 59::230–234.[CrossRef][Web of Science][Medline]

  119. Buchanan RW, Javitt DC, Marder SR, et al. The cognitive and negative symptoms in schizophrenia trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry . In press.

  120. Woods SW, Thomas L, Tully E, et al. Effects of oral glycine in the schizophrenia prodrome. Schizophr Res (2004) 70:(Suppl):79.

  121. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry (2004) 55::452–456.[CrossRef][Web of Science][Medline]

  122. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry (2005) 62::1196–1204.[Abstract/Free Full Text]

  123. Lane HY, Huang CL, Wu PL, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry (2006) 60::645–649.[CrossRef][Web of Science][Medline]

  124. Javitt DC, Sershen H, Hashim A, Lajtha A. Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide. Neuropsychopharmacology (1997) 17::202–204.[CrossRef][Web of Science][Medline]

  125. Atkinson BN, Bell SC, De Vivo M, et al. ALX 5407; a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol (2001) 60::1414–1420.[Abstract/Free Full Text]

  126. Aubrey KR, Vandenberg RJ. N[3-(4’-fluorophenyl)-3-(4’-phenylphenoxy)propyl] sarcosine (NFPS) is a selective persistent inhibitor of glycine transport. Br J Pharmacol (2001) 134::1429–1436.[CrossRef][Web of Science][Medline]

  127. Herdon HJ, Godfrey FM, Brown AM, Coulton S, Evans JR, Cairns WJ. Pharmacological assessment of the role of te glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes. Neuropharmacology (2001) 41::88–96.[CrossRef][Web of Science][Medline]

  128. Harsing LG Jr, Gacsalyi I, Szabo G, et al. The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. Pharmacol Biochem Behav (2003) 74::811–825.[CrossRef][Web of Science][Medline]

  129. Brown A, Carlyle I, Clark J, et al. Discovery and SAR of org 24598-a selective glycine uptake inhibitor. Bioorg Med Chem Lett (2001) 11::2007–2009.[CrossRef][Medline]

  130. Depoortere R, Dargazanli G, Estenne-Bouhtou G, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology (2005) 30::1963–1985.[CrossRef][Web of Science][Medline]

  131. Javitt DC, Balla A, Sershen H, Lajtha A. A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biol Psychiatry (1999) 45::668–679.[CrossRef][Web of Science][Medline]

  132. Bergeron R, Meyer TM, Coyle JT, Greene RW. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci U S A (1998) 95::15730–15734.[Abstract/Free Full Text]

  133. Chen L, Muhlhauser M, Yang CR. Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol (2003) 89::691–703.[Abstract/Free Full Text]

  134. Kinney GG, Sur C, Burno M, et al. The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci (2003) 23::7586–7591.[Abstract/Free Full Text]

  135. Le Pen G, Kew J, Alberati D, Borroni E, Heitz MP, Moreau JL. Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor. Biol Psychiatry (2003) 54::1162–1170.[CrossRef][Web of Science][Medline]

  136. Javitt DC, Balla A, Burch S, Suckow R, Xie S, Sershen H. Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists. Neuropsychopharmacology (2004) 29::300–7.[CrossRef][Web of Science][Medline]

  137. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J Neurosci (1998) 8::2740–2747.

  138. Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA. Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol (2005) 3::e299.[CrossRef][Medline]

  139. Johnson SA, Luu NT, Herbst TA, et al. Synergistic interactions between ampakines and antipsychotic drugs. J Pharmacol Exp Ther (1999) 289::392–397.[Abstract/Free Full Text]

  140. Goff DC, Leahy L, Berman I, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol (2001) 21::484–487.[CrossRef][Web of Science][Medline]

  141. Goff DC, Lamberti JS, Leon AC, et al. A placebo-controlled add-on trial of ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology (2007) In press.

  142. Marenco S, Egan MF, Goldberg TE, et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res (2002) 57::221–226.[CrossRef][Web of Science][Medline]

  143. Marino MJ, Conn PJ. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol (2006) 6::98–102.[CrossRef][Web of Science][Medline]

  144. Schoepp DD. New directions in the treatment of schizophrenia: modulators of mGlu2 and/or mGlu3 receptors. Neuropsychopharmacology (2006) 31::S26.


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