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Sbm074 1.20

Schizophrenia Bulletin Advance Access published July 7, 2007
Schizophrenia Bulletindoi:10.1093/schbul/sbm074 Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia symptoms have been effectively treated.3 Indeed, a meta- analysis of cognitive deficits suggested that indices of cog- Department of Psychiatry, University of California, San Fran- cisco, CA; 3Department of Pharmacology, University of North nitive deficits are much better predictors of functional Carolina School of Medicine, 8032 Burnett-Womack, CB # 7365, outcome than indices from any other symptom domain.4 Furthermore, the severity of cognitive deficits is predictiveof poorer medication compliance,5 overall treatment ad-herence,6 and increased tendency for relapse in first-epi- Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently Until recently, antipsychotic drug development in precede the onset of other positive symptoms, persist schizophrenia has focused mainly on developing drugs even with successful treatment of positive symptoms, and that reduce the positive symptoms of schizophrenia,8 account for a significant portion of functional impairment and indeed, all the current medications appear to be sim- in schizophrenia. While the atypical antipsychotics have ilar in efficacy for reducing positive symptoms in typical produced incremental improvements in the cognitive func- patients with schizophrenia.9,10 In a recent meta-analysis, tion of patients with schizophrenia, overall treatment patients treated with typical antipsychotics were actually remains inadequate. In recent years, there has been an in- shown to have small but detectable improvements in sev- creased interest in developing novel strategies for treating eral cognitive domains11; however, due to extrapyramidal the cognitive deficits in schizophrenia, focusing on amelio- side effects, many patients are also treated with anticho- rating impairments in working memory, attention, and so- linergic agents that are well known to impair memory12 cial cognition. Here we review various molecular targets and global cognitive ability.13 In addition, there is some that are actively being explored for potential drug discov- evidence for the superiority of atypical antipsychotics, ery efforts in schizophrenia and cognition. These molecular such as olanzapine and risperidone, over typicals in im- targets include dopamine receptors in the prefrontal cortex, proving cognitive performance,14–16 though the benefits nicotinic and muscarinic acetylcholine receptors, the gluta- are relatively small and have not been consistently repro- matergic excitatory synapse, various serotonin receptors, duced.17 Overall, the widespread use of the atypical anti- and the g-aminobutyric acid (GABA) system.
psychotics has likely offered some cognitive benefit forpatients with schizophrenia,18 though significant deficits Key words: serotonin/dopamine/glutamate/NMDA/ persist, suggesting a need for directive treatments for en- Due to the continued need for improved treatment of the cognitive impairments in schizophrenia, Wayne Fentonspearheaded the National Institutes of Mental Health’s joint academic and industry initiative termed MATRICS Schizophrenia is characterized by positive symptoms (Measurement and Treatment Research to Improve Cog- such as delusions and hallucinations, negative symptoms nition in Schizophrenia) to facilitate the development of such as avolition and flat affect, and cognitive impair- better treatments targeted at cognition.19 An initial ments. Although Kraepelin,1 with his term ‘‘dementia praecox,’’ characterized the relationship between cogni- identified 7 primary cognitive domains that are crucial tive deficits and schizophrenia nearly a century ago, effec- for developing targets for the treatment of cognition in tive treatments for these deficits have not been developed.
schizophrenia. These domains included working memory, Cognitive dysfunction is estimated to occur in 75%– speed of processing, verbal learning and memory, attention 85% of patients with schizophrenia,2 often precedes the and vigilance, reasoning and problem solving, visual learn- onset of other symptoms,2 and persists even after other ing and memory, and social cognition.20–22 An additionalMATRICS identified pharmacologic strategies that hold promise for To whom correspondence should be addressed; tel: 919-966- 7535, fax: 919-966-5640, e-mail: [email protected]
the treatment of impaired cognition in schizophrenia.
Ó The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
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The primary molecular targets identified included dopa- Table 1. Molecular Targets for Cognitive Enhancement in mine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergicexcitatory synapse, various serotonin receptors, and the c-aminobutyric acid (GABA) system. Below, we review many of the molecular targets being studied for potential drug development strategies aimed at enhancing cognition, both generally and specifically in schizophrenia (table 1).
Acetylcholine is known to play an important role not only in motor function but also in various domains of cognition, particularly attention, learning, and mem- ory.23 Indeed, cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer’s dis- ease and has also been postulated to contribute to the cognitive deficits of various neuropsychiatric disorders, including schizophrenia.23 The basal cholinergic complex sends widely diffuse afferents through 2 projections: the septohippocampal and the nucleus basalis of Meynart cortical pathways.24 The septohippocampal pathway is important in working memory processes through hippo- whereas the nucleus basalis of Meynart cortical pathway is involved in reference memory through long-term infor- mation storage in the neocortex.27,28 Additionally, a role for acetylcholine in the processes of attention has been demonstrated in rats and monkeys.29 Pharmacologically, anticholinergic drugs, like scopolamine, produce learning impairments in healthy subjects similar to those of per- sons with dementia,30 while cholinomimetic drugs, like physostigmine, can significantly enhance the memory Although the degeneration of cholinergic neurons in the basal forebrain and the associated loss of cerebral neuro- transmission that is seen in Alzheimer’s disease are absent in schizophrenia,32,33 there is evidence of decreased nico- tinic34 and muscarinic35 acetylcholine receptors in the cor- tex and hippocampus of individuals with schizophrenia.
Interestingly, in patients with schizophrenia, decreased ac- tivity of choline acetyltransferase, a biosynthetic enzyme for acetylcholine production, was correlated with poorer cognitive functioning as measured by the Clinical Demen- tia Rating.33 In addition, some of the atypical antipsy- chotics, but not typical antipsychotics, can increase the release of acetylcholine in the prefrontal cortex, possiblycontributing to their modest enhancement of cognition in Note: D, dopamine; n/a, clinical evidence not available to date; schizophrenia.36 Thus, various targets within the cholin- COMT, catechol-O-methyltransferase; 5-HT, serotonin; IBS, ergic system are being investigated as potential enhancers irritable bowel syndrome; DMXB-A, 3-2,4-dimethoxybenzylidene anabaseine; M, muscarinic; NMDA, N-methyl-D-aspartate; GlyT,glycine transporter; mGluR, metabotropic glutamate receptor;GABA, c-aminobutyric acid.
aThe term ‘‘agonist’’ is used here to refer to agonists, partial Cholinesterase inhibitors, such as donepezil and rivastig- agonists, and positive allosteric modulators.
mine, are currently the main pharmacologic approach to withdrawn due to increase in adverse cardiovascular events.
Molecular Targets for Cognition in Schizophrenia the treatment of Alzheimer’s disease and have been uals may be ‘‘self-medicating’’ with nicotine.50,51 Indeed, shown to slow the cognitive decline in this neurodegen- nicotine administration has been shown to improve var- erative disease.37 As such, it has been proposed that ious measures of cognition that may ease some of the side cholinesterase inhibitors may also be useful in the treat- effects of antipsychotic medications.51 For example, in ment of the cognitive dysfunction in schizophrenia.38 patients with schizophrenia, a nicotine transdermal patch Acetylcholinesterase and butyrylcholinesterase are pres- could dose dependently reverse haloperidol-induced ent in a wide variety of tissues and are broadly distributed impairments in working memory, attention, and reaction in the brain. Inhibition of cholinesterases increases the time52 and has been shown to reduce haloperidol-induced synaptic concentration of acetylcholine, thereby enhanc- bradykinesia and rigidity compared with a placebo ing and prolonging the action of acetylcholine on both patch.53 However, other studies have been mixed.54 Inter- muscarinic and nicotinic receptors. Therefore, cholines- estingly, in one study,55 some of the modest effects of cig- terase inhibitors act as indirect cholinergic agonists at arette smoking on clinical and cognitive outcome measures could also be improved by smoking denicoti- Following the administration of atypical antipsychotic nized cigarettes, suggesting that nonnicotine components treatment, cholinesterase inhibitors can increase the con- of cigarette smoke may also contribute.55 Overall, while centration of acetylcholine in the medial prefrontal cortex research on nicotinic treatment of individuals with by 2- to 3-fold36 and have been demonstrated to produce schizophrenia has shown that, in single administrations, some functional normalization of brain activity during nicotine improves some aspects of cognition, additional verbal fluency task performance of schizophrenic patients administrations are not effective due to rapid desensitiza- characterized by a significant increase in frontal lobe and tion of nicotinic receptors.42 Thus, considerable research cingulate activity on functional magnetic resonance imag- is exploring the potential use of nicotinic agents, partic- ing (fMRI).39 As such, in recent years there have been ularly partial agonists and allosteric modulators at var- multiple small randomized controlled trials of cholines- ious nicotinic receptor subunits that would be less terase inhibitors in patients with schizophrenia, though likely to cause rapid receptor desensitization.
results have been disappointing and inconsistent.40 It Nicotinic acetylcholine receptors are ionotropic recep- has been suggested that the lack of consistent effects of tors with a pentameric structure composed of alpha (a2 to cholinesterase inhibitors may be due to the high rate of a9) and beta (b2 to b4) subunits and are expressed at high cigarette smoking among patients with schizophrenia41 levels in the hippocampus, cortex, striatum, and thala- and subsequent desensitization of nicotinic receptors,42 mus.34,56 The 2 most prevalent nicotinic receptors are thus rendering increased acetylcholine levels ineffective.43 the a4b2, which is a high-affinity receptor, and the a7, Indeed, galantamine, an acetylcholinesterase inhibitor which is a low-affinity nicotinic receptor, both of which that is also an allosteric potentiator of a7 nicotinic recep- have been shown to have reduced numbers in patients tors,44,45 does not cause a7 receptor desensitization and with schizophrenia.34,56 In addition, functional polymor- has been shown to enhance cognitive functioning of phisms exist in the promoter region of the a7 receptor that schizophrenic patients in a 4-week double-blind placebo have shown genetic linkage in schizophrenia.57,58 controlled trial.46 Interestingly, galantamine produced The a7 nicotinic receptor subtype is a highly studied tar- cognitive enhancement in schizophrenic patients despite get for the development of drugs for cognitive enhance- the fact that all the patients smoked at least 10 cigarettes ment. Studies in rodents have shown that antagonists per day.46 Unfortunately, despite these initial positive at the a7 nicotinic receptor induce sensory gating deficits findings, subsequent results with galantamine have similar to those seen in schizophrenia,59 a hippocampal been mixed.47–49 Thus, while pure cholinesterase inhibi- phenomenon manifested as an inability to attend appro- tors may be of minimal benefit for enhancing cognition priately to sensory stimuli.60 Sensory gating deficits may in patients with schizophrenia, possibly due to desensiti- strongly impact cognitive performance, and it has been zation of their a7 nicotinic receptors from cigarette smok- shown that smoking transiently normalizes these sensory ing, further study may be warranted with combined gating deficits.60 In addition, agonists at a7 receptors such acetylcholinesterase inhibitors and allosteric potentiators as 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A) of the nicotinic receptor in schizophrenia. However, it is can normalize the auditory gating deficits in rodents.61 likely that selective agents at various nicotinic and mus- Moreover, DMXB-A had a positive effect on a cognitive carinic receptors may be a more effective approach to de- battery in a small proof-of-concept trial in humans,62 and veloping drugs for treatment of the cognitive impairment additional clinical trials of a7 receptor agonists are under- way. However, there is concern that long-term use of a7agonists may induce the desensitization of nicotinic recep- tors, leading to a limited duration of efficacy.63 Thus, It is well known that the smoking rates in individuals with further development of a7 receptor partial agonists (eg, schizophrenia are significantly higher than in the general GTS-21) and allosteric potentiators (eg, galantamine) population, and some have suggested that these individ- that induce minimal receptor desensitization is warranted.
In addition to a7 receptors, it has been suggested that NDMC is the major active metabolic of clozapine and a4b2 nicotinic receptors are involved in cognition.64 In- has been reported to be a potent M1 agonist that prefer- deed, a4b2 receptors are considered to represent more entially binds to M1 receptors vs clozapine,83 although than 90% of the high-affinity nicotine-binding sites in more comprehensive studies fail to demonstrate selectiv- the rat brain,65 and decreased levels of a4b2 receptor ity of NDMC for M1 receptors.84 In addition, NDMC binding have been found in the hippocampus of patients has high affinities for 5-HT2A and 5-HT2C receptors with schizophrenia.56 Furthermore, agonists of a4b2 and is a partial agonist at D2, D3 receptors85,86 and d-opi- receptors, such as RJR2403 and SIB-1553A, can produce oid receptors,87 suggesting that this metabolite of cloza- a significant and long-lasting improvement of memory in pine may have antipsychotic and cognition-enhancing rats and monkeys.66–68 Additionally, a4b2 agonists have properties via a number of mechanisms. Furthermore, been shown to stimulate the release of dopamine, norepi- NDMC, but not clozapine, increases release of dopamine nephrine, and acetylcholine in the hippocampus and and acetylcholine in the prefrontal cortex and the hippo- frontal cortex in rats.66 Thus, nicotinic a4b2 receptor ago- campus88 and potentiates NMDA receptor activity in the nists may be of therapeutic benefit for the treatment of hippocampus.83 Thus, the cognitive enhancement ob- the cognitive deficits in schizophrenia by several mecha- served with clozapine could actually be due to its metab- nisms. In addition to a7 and a4b2 receptors, other nico- olite NDMC via an uncertain mechanism.
tinic receptors, such as a3- and a6-containing receptors, Indeed, NDMC (ACP-104) and other M1 receptor ago- may be involved in cognitive performance; however, nists are in clinical trials as potential treatments of the studies are limited due to the lack of selective agonists cognitive dysfunction in schizophrenia. Xanomeline, a and antagonists for these receptors.
nonselective M1 and M4 muscarinic agonist with potentactions at a variety of additional nonmuscarinic receptorsincluding 5-HT1A and 5-HT2A receptors,89 improved cog- nition and psychotic-like symptoms in Alzheimer’s dis- In addition to the ionotropic nicotinic receptors, numerous ease.90 In addition, monotherapy with xanomeline studies have implicated metabotropic muscarinic acetyl- resulted in an improvement of positive symptoms and choline receptors in schizophrenia. Muscarinic receptors cognitive function in 20 subjects with schizophrenia91 are G protein–coupled receptors69 found widely through- but was discontinued due to poor tolerability.92 The rel- out the central nervous system on both cholinergic and non- atively nonselective actions of xanomeline and NMDC cholinergic cells where they function as both autoreceptors at a number of receptors (http://pdsp.med.unc.edu/ and heteroreceptors.70–72 Of the 5 genetically distinct sub- pdsp.php) should engender caution among schizophrenia types of muscarinic receptors (M1–M5), the M1 receptor has researchers for embracing positive data from xanomeline been most closely linked to cognition and schizophrenia.73 and NMDC studies as being specifically indicative of Indeed, the M1 receptor subtype is the most abundant of the a role for M1 receptors in schizophrenia.
muscarinic receptors in forebrain and hippocampus,74,75 Overall, evidence suggests that M1 receptor agonists brain regions crucial to normal cognitive functions. In ad- could be useful in treating various symptom domains dition, decreased M1 receptor binding has been reported in in schizophrenia, though the roles of the other muscarinic postmortem studies of the prefrontal cortex, hippocampus, receptor subtypes are less clear. M5 receptors, for exam- and striatum from patients with schizophrenia,76–78 that is, ple, may be relevant to schizophrenia as they are located importantly, not due to chronic antipsychotic treat- in the brainstem and midbrain, where they have an effect ment.35,77,79 Interestingly, M1 receptor–deficient mice dem- on dopamine release.93 Indeed, xanomeline is also an an- onstrate deficits in working memory and remote reference tagonist at M5 receptors, suggesting that blockade of M5 memory indicative of impaired hippocampal-cortical inter- may be involved in the benefits seen with xanomeline.94 actions.80 Together, these results suggest that alterations in In addition, M4 receptor knockout mice have impair- central M1receptorsmayhavearoleinthepathophysiology ments of cognitive performance and elevated levels of do- of schizophrenia and that M1 receptor agonists may be ben- pamine in the nucleus accumbens, suggesting a potential eficial in treating schizophrenia, particularly the cognitive role for M4 receptor agonists in treating both the positive and cognitive symptoms of schizophrenia.95,96 As selec- Action at M1 receptors has been proposed to be a tive agonists at muscarinic receptor subtypes have been major contributor to the cognition-enhancing effects of difficult to develop, positive allosteric modulators are clozapine,81 despite the fact that clozapine is an exceed- also being explored as potential therapeutic agents.
ingly weak partial agonist at M1 and other muscarinicreceptors.73,82 Thus, attention has focused on various clozapine metabolites including clozapine-N-oxide andN-desmethylclozapine (NDMC). Clozapine-N-oxide is Glutamate is the primary excitatory neurotransmitter for inactive while NDMC has actions at many receptors approximately 60% of the neurons in the mammalian brain, including all cortical pyramidal neurons,97 and Molecular Targets for Cognition in Schizophrenia plays a principal role in modulating long-term potentia- and glycine binding, with glycine binding affecting chan- tion, a likely key cellular mechanism for learning and nel open time and desensitization rate but not inducing memory.98,99 Glutamate mediates fast excitatory postsyn- channel opening itself.100 In addition, NMDA receptor ac- aptic potentials by acting on 3 ionotropic receptors, which tivity can be allosterically modulated by multiple other are differentiated based upon sensitivity to the synthetic substances, including Mg2þ, polyamines, and protons.112 glutamate derivatives N-methyl-D-aspartate (NMDA), Thus, while direct agonists of the glutamate-binding site of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic the NMDA receptor may not be clinically feasible due to acid (AMPA), and kainate.100 In addition, glutamate the risk of excess excitation and neurotoxicity, the alloste- exerts slower modulatory effects by acting on various ric sites on the NMDA receptor complex, particularly the G protein–coupled metabotropic glutamate receptors glycine-binding site, are promising targets for drug devel- (mGluRs).101 For example, mGluR2 and mGluR3 recep- opment. Indeed, chronic treatment of rodents with glycine tors modulate the release of glutamate, whereas the has not been found to induce excitotoxicity.113,114 mGluR5 receptor potentiates the duration of NMDA re- Compounds that target the glycine site of the NMDA ceptor–dependent excitatory postsynaptic potentials.102 receptor complex have been studied in multiple small It has been hypothesized for decades that some defi- clinical trials. These include glycine115 and D-serine,116 ciency in NMDA function might play a role in the patho- which are endogenous agonists at the glycine site of physiology of schizophrenia.103 Since the 1950s, the the NMDA receptor complex; D-alanine; and D-cycloser- NMDA receptor antagonists phencyclidine (PCP) and ine, an antituberculosis drug that also binds to the glycine ketamine were known to produce a large range of schizo- modulatory site where it functions as a partial agonist.117 phrenia-like symptoms including psychotic symptoms, In most of these studies, the test compound was admin- negative symptoms, and cognitive dysfunction,103–105 istered along with either a typical or atypical antipsy- and it has been suggested that augmenting NMDA recep- chotic, and there appears to be significant effects at tor activity may have therapeutic potential in schizophre- reducing negative symptoms and cognitive impairment nia.100 Indeed, some of the atypical antipsychotics, but in patients with schizophrenia.118 Of the 4 agents, D-cy- not typical antipsychotics, have been shown in preclinical closerine has been the least efficacious, likely due to it be- models to reverse the effects of ketamine and PCP,106–109 ing a partial agonist that acts as an antagonist at high presumably through indirect activation of NMDA recep- doses. Interestingly, when used concurrently with cloza- tors mediated by other neurotransmitter systems.83 It is pine, glycine119 and D-serine120 have been reported to be also important to note that a competing hypothesis sug- ineffective while D-cycloserine seemed to worsen symp- gests that a hyperactivity of glutamatergic neurotransmis- toms,121 possibly because clozapine may already enhance sion is involved in the psychopathology of schizophrenia, glycine and glutamate neurotransmission. Overall, ago- nists at the glycine allosteric site of the NMDA glutamate approaches being explored.100 Indeed, glutamatergic exci- receptor hold promise in the treatment of the negative totoxicity is thought to be a factor in the neurodegenera- and cognitive symptoms of schizophrenia, possibly as tion of Alzheimer’s disease110 and a weak NMDA receptor an augmentation of currently existing antipsychotics.
antagonist, memantine, has shown efficacy in slowing cog- A potential limitation of targeting the glycine modula- nitive decline in moderate to advanced Alzheimer’s dis- tory site is that the glycine site is probably half-saturated ease.111 Thus, the glutamate system, especially its during physiologic conditions, suggesting that treatments NMDA-dependent components, is complex, and while targeting the glycine site would theoretically only be able small increases in NMDA-dependent glutamate neuro- to effectively double NMDA neurotransmission.118 In transmission might be cognitively enhancing, too much ac- addition, both glycine and D-serine must be given at tivation may result in neurodegeneration. Fortunately, the gram-level doses to significantly elevate central nervous glutamatergic excitatory synapse offers multiple targets system levels, and attempts to modify glycine or D-serine for drug development to provide the precise level of en- to produce synthetic glycine-site agonists, have, thus far, hancement to improve cognition without excitotoxicity.
been unsuccessful. Thus, indirect approaches to activate Thus, we briefly review below various approaches being NMDA receptors are being explored, such as increasing explored for modulating NMDA receptor neurotransmis- extracellular glycine and glutamate and by modulating sion and discuss approaches aimed at other glutamatergic An indirect approach being explored to boost NMDA NMDA glutamate receptors are ligand-gated ion chan- activity via the glycine allosteric site is to increase synap- nels with a primary glutamate-binding site and an allo- tic glycine by inhibiting the glycine transporter. The gly- steric glycine-binding site.100 Interestingly, the opening cine transporters, GlyT1 and GlyT2, have been identified of the NMDA channel appears to require both glutamate on both neuronal and glial cells in the central nervous system, where they are suggested to control the extracel- ampakines improve performance in rodents on a variety lular concentration of glycine.122 Thus, blockade of gly- of memory tasks including spatial mazes135,136 and cine transporters is predicted to increase extracellular learned fear137 and have been shown to be effective in re- glycine and thus enhance NMDA receptor neurotrans- ducing age-associated memory deficits in rats.138 In a clin- mission. Indeed, preclinical data suggest that inhibition ical trial of schizophrenia patients on clozapine, of glycine reuptake represents a feasible approach to coadministration of the ampakine CX-516 yielded signif- enhance NMDA receptor activity and possibly be thera- icant improvements in memory and attention;139 how- peutic in schizophrenia.100 For example, selective, high- affinity inhibitors of the glycine transporter, including schizophrenia showed no clear beneficial effects.140 Im- Org-24598, N-[3-(4#-fluorophenyl)-3-(4#-phenylphenox- portantly, higher potency ampakines are currently under y)propyl] sarcosine, and SSR-504734, have been found clinical development as both monotherapy for schizo- to reverse PCP-induced hyperactivity and dopaminergic phrenia and adjunctive treatment for cognitive dysfunc- hyperreactivity in rodents.123,124 Furthermore, the gly- tion, though results of trials are not yet available. A cine transport inhibitor glycyldodecylamide attenuated higher potency ampakine, farampator, has been tested PCP-induced hyperactivity more potently than adminis- in healthy elderly volunteers and improved short-term memory but appeared to impair episodic memory,141 Clinical trials to date, however, have only studied the and thus, it remains unclear if modulation of AMPA low-potency glycine transport inhibitor sarcosine (N- receptors has therapeutic value in the treatment of the methyl glycine). In a clinical trial of sarcosine added to cognitive dysfunction in schizophrenia although this is the stable antipsychotic regimen of patient with schizo- a highly active area of current research.
phrenia, there was a highly significant reduction in neg-ative symptoms, along with smaller but significant reductions in positive and cognitive symptoms.127 Inter- Agents acting at mGluRs, which serve to regulate gluta- estingly, a subsequent study with patients on clozapine matergic neurotransmission both pre- and postsynapti- found no improvement of symptoms with the addition cally, are currently in preclinical development for of sarcosine, a result similar to studies with the treatment of the cognitive dysfunction in schizophrenia.
NMDA glycine site agonists.128 These results strongly There are 8 subtypes of mGluRs (mGluR1–8) which are suggest a role of glycine transport inhibitors in the treat- categorized into 3 groups according to their second mes- ment of schizophrenia, though results of trials with selec- senger-coupling and ligand-binding profiles with group I tive, high-potency inhibitors are anticipated.
receptors (mGluR1 and mGluR5) primarily being stud-ied for cognitive enhancement in schizophrenia.102 Group I receptors, particularly mGluR5, function pre-dominantly to potentiate both presynaptic glutamate re- Another glutamatergic approach to drug development lease and postsynaptic NMDA neurotransmission,142 for cognitive enhancement in schizophrenia has been and mGluR5 receptors show significant colocalization the development of compounds that stimulate AMPA with NMDA receptors in cortical pyramidal neurons.143 and kainate glutamate receptors. AMPA and kainate Together, these findings suggest that mGluR5 agonism receptors mediate the majority of the fast glutamatergic may enhance NMDA activity and improve memory signaling in the brain, and AMPA receptors work heavily and cognition.142 Indeed, selective mGluR5 agonists in concert with NMDA receptors.100 AMPA receptors were found to inhibit PCP-induced dopamine release provide the primary depolarization necessary to activate in the rodent prefrontal cortex.144 Direct mGluR5 ago- NMDA receptors, while NMDA receptors are required nists, however, are likely to induce receptor desensitiza- for proper incorporation of AMPA receptors into the tion limiting their therapeutic usefulness. Thus, selective postsynaptic membrane, a process involved in synaptic allosteric potentiators of mGluRs have recently been plasticity.129 Thus, activation of AMPA receptors is developed and hold promise as therapeutic agents.145,146 likely critically important for learning and memory; how- Indeed, preliminary positive results with an mGluR2/3 ever, direct AMPA agonists are unlikely to be therapeu- agonist in phase II trials have been reported (http:// tically useful as AMPA receptors rapidly desensitize after www.prnewswire.com/cgi-bin/micro_stories.pl?ACCT= 916306&TICK=LLY&STORY=/www/story/12-07-2006/ In an attempt to avoid desensitization of AMPA recep- 0004487009&EDATE=Decþ7,þ2006).
tors, allosteric potentiators of AMPA receptor function,a class of compounds termed ampakines, are being stud- ied as potential treatments for enhancing cognition inschizophrenia.131,132 Indeed, ampakines have been shown Dopamine projections to the prefrontal cortex compris- to enhance glutamatergic transmission and facilitate ing the mesocortical dopamine system are essential for long-term potentiation in rodents.133,134 Furthermore, normal cognition.147,148 Thus, it has been hypothesized Molecular Targets for Cognition in Schizophrenia that decreased dopaminergic neurotransmission in the working memory.158 In addition, chronic treatment with prefrontal cortex contributes to the cognitive deficits ob- a D1 agonist may actually lead to the downregulation of served in schizophrenia, especially those related to exec- D1 receptors which could, potentially, worsen cognition utive functions and working memory.149–151 Indeed, in the long term. Thus, an optimized level of D1 receptor postmortem and in vivo imaging studies have linked activation at the apex of the ‘‘inverted-U’’ may be re- prefrontal dopamine dysfunction to cognitive impair- quired to obtain maximal cognitive benefits,157 which ment,151,152 and various studies have demonstrated may be accomplished by partial agonists or an intermit- that direct and indirect dopamine agonists can improve tent pattern of administration.161,165 An additional ob- prefrontal cortex cognitive functions in humans.153,154 stacle is the powerful hypotensive effects of direct- However, it seems that precise regulation of prefrontal acting D1 agonists on peripheral D1 receptors,166 which dopaminergic tone is essential as, in addition to insuffi- may necessitate the use of indirect D1-activating agents cient dopamine, excessive prefrontal dopamine (eg, such as catechol-O-methyltransferase (COMT) inhibitors resulting from acute stress) may be deleterious to cogni- tion.155–157 Thus, dopamine function in the prefrontalcortex seems to follow an ‘‘inverted-U’’ dose-responsecurve whereby increases or decreases from an optimal level result in cognitive impairment.158 Additionally, in- The high affinity of clozapine for dopamine D4 receptors direct dopamine agonists could potentially exacerbate led to speculation that D4 receptors may be clozapine’s psychosis by increasing neurotransmission at mesolimbic ‘‘magic receptor.’’167 Clinical trials of selective D4 antag- onists, however, have not demonstrated any appreciableefficacy in the treatment of acute schizophrenia,168–170though it is possible that D4 receptor blockade in collab- oration with action at other neurotransmitter receptors Dopamine D1 receptors are expressed at high levels on may be clinically beneficial. Indeed, studies of the phys- the distal dendrites of pyramidal neurons in the prefron- iological roles for the D4 receptor are finding that D4 tal cortex that are thought to be involved in working receptors may play an important role in impulsivity memory processes.158,159 Indeed, evidence suggests an important role of dopamine D1 receptors in the cognitive The mechanism by which D4 blockade could improve dysfunction of schizophrenia.138 For example, there is cognition is not fully known,172 though D4 receptors are a decreased level of D1 receptor–like binding in the pre- present on both pyramidal neurons and GABA-produc- frontal cortex of drug-naive patients with schizophrenia ing interneurons in the prefrontal cortex and hippocam- as measured with positron emission tomography imag- pus,173 areas important for cognitive function. Studies ing, and this decrease was found to be correlated with have demonstrated that activation of D4 receptors the severity of negative symptoms and cognitive dysfunc- decreases NMDA receptor activity in the hippocam- tion but not with the severity of positive symptoms.160 In pus174 and inhibits glutamatergic signaling in the prefron- addition, in nonhuman primates, chronic blockade of D2 tal cortex.175 Additionally, D4 receptor knockout mice receptors results in a downregulation of D1 receptors in show enhanced activity of cortical pyramidal neurons, the prefrontal cortex and consequently produces severe an effect mimicked in wild-type mice by administration impairments in working memory.161 This downregula- of the D4 antagonist PNU-101387G.175 Together, these tion of D1 receptors may explain why long-term treat- results suggest that D4 antagonism may be a valuable ap- ment with typical antipsychotics can contribute to the proach to improve cognition in schizophrenia. Indeed, cognitive dysfunction in schizophrenia. Thus, significant the D4 antagonist NDG96-1 was reported to reverse efforts are underway to examine the possible role of D1 PCP-induced deficits in object retrieval tasks in mon- receptor agonists in treating cognitive dysfunction in keys,172 and another D4 antagonist, PNU-101387G, re- schizophrenia. Indeed, low doses of selective D1 agonists, versed deficits in the delayed response task induced by such as dihydrexidine, A77636, and SKF81297, have the pharmacologic stressor FG7142 (a benzodiazepine cognition-enhancing actions in nonhuman primates,162–164 inverse agonist).176 Interestingly, PCP-induced cognitive and short-term administration of the D1 selective agonist, deficits are exacerbated by haloperidol, suggesting that ABT-431, reversed the cognitive deficits in monkeys trea- strong blockade of other dopamine receptors may ted chronically with a D2 receptor antagonist.161 counter the beneficial effects of D4 blockade on cognitive Although novel compounds that, directly or indirectly, stimulate D1 receptors may be of immense value in treat- Seemingly contradictory evidence also suggests that D4 ing cognitive deficits in schizophrenia, several potential receptor agonists may improve cognitive function. For pitfalls may need to be overcome. First, D1 receptor ac- example, the selective D4 agonist A-412997 showed tivity follows the ‘‘inverted-U’’ dose-response curve, dose-dependent improvement in social recognition in where either too little or too much D1 stimulation impairs rats, a model of short-term memory,177 and the D4 agonist PD168077 was shown to facilitate memory con- may have improved cognitive response to clozapine.195 In- solidation of an inhibitory avoidance learned response in terestingly, a recent proof-of-concept experiment in mice.178 These effects have been hypothesized to be due normal human subjects treated with tolcapone demon- to D4 receptor modulation of inhibitory GABAergic sig- strated significant improvements on measures of executive naling in the prefrontal cortex.179 Indeed, the D4 agonist function and verbal episodic memory in individuals with PD168077 reduces GABAA inhibitory currents in pyra- a Val/Val genotype but a diminished performance of indi- midal neurons, which could be blocked by the D4 antag- viduals with the Met/Met genotype.196 Thus, overall, the onist L-745870 as well as clozapine.179 Thus, in contrast potential of pharmacologic inhibition of COMT in the to D4 antagonist–induced enhancement of NMDA cur- long-term treatment of the cognitive dysfunction in schizo- rents in the hippocampus, D4 agonists may suppress GABAA inhibitory currents in the prefrontal cortexand thereby indirectly enhance cortical excitability.
Taken together, D4 receptor–selective agents may be valuable in the treatment of the cognitive deficits inschizophrenia, though a balance between D modulation of prefrontal GABAA and hippocampal 5-HT2A receptors are particularly abundant in the pyra- midal neurons from cortical layer V,197 where they havebeen described to colocalize with NMDA glutamatereceptors,198,199 suggesting a role in modulating cognitive functions. Indeed, studies have demonstrated that 5- COMT is a postsynaptic enzyme that methylates and HT2A receptors interact with postsynaptic density pro- thereby deactivates synaptically released catecholamines, tein 95, a protein involved in anchoring NMDA receptors particularly dopamine.180 Historically, monoamine oxi- to postsynaptic densities,200 and it has been suggested dase was considered the primary enzyme for the initial that activation of 5-HT2A receptors increases the release deactivation of synaptic dopamine,181 though mounting of glutamate onto pyramidal cells.201 Interestingly, the evidence suggests that COMT may be especially impor- selective 5-HT2A receptor antagonist M100907 blocked tant for the breakdown of dopamine, particularly in the the cognition-impairing effects of MK-801, an NMDA prefrontal cortex.182 For example, COMT knockout receptor antagonist.202,203 Similar findings have been mice show increased baseline levels of dopamine, but reported for another 5-HT2A antagonist AC-90179.204 not other catecholamines such as norepinephrine, specif- Taken together, these studies suggest an intimate associ- ically in the frontal cortex.183 In addition, the COMT ation between NMDA and 5-HT2A receptors and imply knockout mice also showed enhanced memory perfor- that drugs with potent 5-HT2A antagonistic actions may mance,183 suggesting a potential role of COMT inhibition prove beneficial at improving cognition in schizophrenia, in improving cognition. Indeed, a selective, reversible in- perhaps by normalizing NMDA receptor functioning.203 hibitor of COMT, tolcapone, has been reported to im- In addition, 5-HT2A receptors are located on dopami- prove working memory in rodents184 and has been nergic neurons in the ventral tegmental area,205 where shown to improve cognitive dysfunction in patients they may modulate dopamine neuronal activity.206 In- with advanced Parkinson’s disease,185 though use is lim- deed, it is likely that a predominant role of 5-HT2A recep- ited due to a risk of liver failure.186 Other COMT inhib- tors in antipsychotic action is to modulate dopaminergic itors are currently being investigated for treatment of the tone, particularly along the mesocortical pathway.206–208 cognitive dysfunction in schizophrenia.
For example, clozapine, olanzapine, and ziprasidone, but Interestingly, a common single nucleotide polymor- not haloperidol or risperidone, can preferentially augment phism in the gene encoding COMT, Val158Met, results dopamine and norepinephrine release in the prefrontal cor- in the transcription of a variant of the COMT enzyme tex relative to the subcortical areas.209 In rats, however, re- with approximately 40% less enzymatic activity in peated administration of the selective 5-HT2A antagonist humans.187 The reduced COMT enzymatic activity asso- M100907 can alter the activity of midbrain dopamine ciated with the Met variant presumably results in greater neurons in rats, though there is disagreement as to whether availability of dopamine in the prefrontal cortex and, thus, cortical dopamine levels are potentiated210 or inhibited.211 may improve cognition, hypotheses supported by findings Thus, it has been hypothesized that the ultimate effect of from the COMT knockout mice,183 and an fMRI study in 5-HT2A antagonists on dopaminergic neurotransmission humans.188 Furthermore, the COMT locus at chromo- some 22q11 has been identified as a susceptibility locus Clinical studies with selective 5-HT2A receptor com- for schizophrenia in several linkage studies189,190 and 2 pounds have also demonstrated a role of 5-HT2A receptors meta-analyzes,189,191 though this remains controver- in cognitive functioning in schizophrenia. For example, in sial.192–194 However, accumulating evidence predicts a study of 30 hospitalized patients with schizophrenia, ad- that patients with schizophrenia who have the Met allele ministration of mianserin, a 5-HT2A/2C and a2-adrenergic Molecular Targets for Cognition in Schizophrenia antagonist, improved scores on the Automated Neuropsy- in patients with schizophrenia.229,230 Interestingly, the 5- chological Assessment Metrics at 4 weeks, though no sig- HT1A agonist NAE-086 actually induced hallucinations nificant improvement was found on the Wisconsin Card and nightmares in normal individuals after repeated Sorting Test.213 These results suggest that 5-HT2A receptor doses,231 suggesting that 5-HT1A agonists may not be tol- antagonism may improve cognitive function in schizo- erated well in schizophrenic individuals. Taken together, phrenia,214,215 though additional clinical studies are these results demonstrate that additional clinical studies needed. However, because nearly all approved atypical an- are needed but suggest that 5-HT1A receptors may need tipsychotic drugs have potent 5-HT2A antagonist actions, to be differently modulated to optimally enhance cognition it is unlikely that adding on a drug with potent 5-HT2A an- in various pathologic conditions (ie, dementia vs schizo- tagonism will provide any significant boosting of cognition phrenia) and that 5-HT1A partial agonists with a high level in treated patients.212 The potential cognition-enhancing of efficacy may present a significant risk of exacerbating effects resulting from 5-HT2A receptor antagonism with the currently available atypical antipsychotics may bemasked by other drug actions, such as anticholinergic effects, known to cause cognitive impairment.216 Serotonin 5-HT4 receptors are found at high densities in the hippocampus, frontal cortex, and amygdala, suggest- ing a role of these receptors in cognitive functions.232,233 5-HT1A receptors are densely concentrated in the hippo- campus, lateral septum, amygdala, and cortical limbic 4 receptors have been shown to be markedly decreased in patients with Alzheimer’s disease.234 In addi- areas, as well as both the dorsal and median raphe nu- 4 receptor agonists have shown promise in the treatment of cognitive impairment by enhancing choliner- as somatic autoreceptors providing inhibitory feedback gic transmission in the hippocampus.212,235 For example, control of 5-HT release.219 However, the highest concen- 4 receptor partial agonist, SL65.0155, improved learning and memory performance in chemically induced campal pyramidal neurons220 suggesting a role of 5-HT1A rat model of amnesia,236 and this improvement may be receptors in mediating cognitive functions. 5-HT1A recep- due in part to lengthening of the excitatory postsynaptic tors on cortical pyramidal neurons are colocalized with potential in hippocampal CA1 pyramidal neurons.237 5-HT2A receptors,221 though while 5-HT2A receptor acti- Interestingly, a recent study also showed that the activation vation is excitatory, 5-HT1A receptor activation inhibits receptors in a neuronal culture inhibited the secretion of b-amyloid peptide and enhanced neu- Because they act on different locations of the receptors, 1A partial agonists and full antagonists have agonists are mostly being studied for their role in the shown a positive effect on cognitive activity in animals.223 treatment of Alzheimer’s disease, they may also be of Thus, 5-HT1A partial agonists, presumably acting on py- benefit in the treatment of the cognitive dysfunction ramidal neurons, improve cognition in animals, while 5- HT1A antagonists also improve cognition, probably byacting at the raphe autoreceptors.208,223 Indeed, atypicalantipsychotic drugs modestly enhance cognition, and sev- eral atypical antipsychotic drugs have 5-HT1A partial ag- Several atypical antipsychotics, including clozapine and onist actions (eg, aripiprazole, clozapine, olanzapine, olanzapine, and some tricyclic antidepressants, such as ziprasidone, quetiapine),224,225 while others are 5-HT1A amoxapine, amitriptyline, and clomipramine, were found antagonists (eg, risperidone and sertindole).224 Preclinical to have high affinity for 5-HT6 receptors239–241 prompting experiments also show that both 5-HT1A partial agonists significant efforts to understand its possible role in schizo- and antagonists can improve cognition. For example, phrenia and other neuropsychiatric disorders. When anti- intraprefrontal infusion of 8-OH-DPAT, a nonselective sense oligonucleotides were used to decrease the level of 5- 5-HT1A agonist, improved visual-spatial attention and HT6 receptor expression in rats, the rats exhibited an in- decreased impulsivity in rats,226 while WAY100635, creased number of yawns and stretches that could be a 5-HT1A antagonist, blocked the deleterious effects of blocked by atropine, suggesting a role of the 5-HT6 recep- MK-801 and NMDA antagonist in rats.227 Thus, the pre- tor in the control of cholinergic neurotransmission.242,243 clinical literature is mixed regarding whether 5-HT1A ago- In addition, the selective 5-HT6 receptor antagonist SB- nists or antagonists enhance cognition.
271046 has been shown to improve memory retention in Clinical data in humans are equally mixed. For example, the water maze test of spatial learning and memory.244,245 activating 5-HT1A receptors with a single dose of tando- Thus, it appears likely that 5-HT6 receptors may have an spirone, a 5-HT1A partial agonist, diminished explicit important future role in the treatment of cognitive deficits memory function228 in demented patients, though chronic in neuropsychiatric illnesses such as Alzheimer’s disease administration of tandospirone enhanced verbal memory The 5-HT7 receptor exhibits a distinct distribution in the Appropriately synchronized GABA neurotransmission central nervous system with relatively high levels in the in the dorsolateral prefrontal cortex is required for ade- thalamus, hypothalamus, and hippocampus and lower quate working memory,262 suggesting that impairments levels in the cortex and amygdala.246–248 In addition to in GABA-mediated inhibition could contribute to the possible roles in regulating circadian rhythms and cognitive impairments in schizophrenia. Indeed, post- sleep,249–251 5-HT7 receptors may also have an important mortem studies have shown reduced GABAergic trans- role in hippocampus-dependent functions such as learn- mission in schizophrenia.263–265 In addition, recent ing and memory.252 For example, 5-HT7 receptor knock- observations266,267 have noted decreases in messenger out mice have been found to exhibit a specific impairment RNA levels for glutamic acid decarboxylase 67, the syn- in contextual fear conditioning in which the animal learns thetic enzyme for GABA, selectively in the prefrontal to associate the environment with an aversive stimulus, cortex of patients with schizophrenia. Interestingly, a re- a process generally believed to require the hippocam- cent study revealed that GABA alterations in the dorso- pus.253 Electrophysiological studies have also shown lateral prefrontal cortex of schizophrenic patients may be that 5-HT7 receptor activation modulates the excitability restricted to certain cell classes, such as the chandelier and intracellular signaling of pyramidal neurons in the cells, which synchronize the activation of pyramidal neu- CA1 region of the hippocampus.254,255 Additionally, in rons via GABAA receptor subtypes.268 Thus, the use of 5-HT7 receptor knockout mice, there is a reduced ability new benzodiazepine-like agents—selective for the a2 sub- to induce long-term potentiation in the CA1 region of the unit of the GABAA receptor—in cognitive disorders hippocampus.253 Together, these findings suggest an im- could be both interesting and revealing. Indeed, there is portant role for the 5-HT7 receptor in hippocampus-de- evidence that reduced GABA neurotransmission in chan- pendent functions, including learning and memory.252 delier cells may be secondary to altered NMDA receptor Thus, selective 5-HT7 receptor activators might prove function and could represent a ‘‘final common pathway’’ therapeutically useful for the treatment of the cognitive of prefrontal dysfunction in schizophrenia.269 Thus, drugs targeted to mitigate the disturbances in inhibition might beparticularly effective in improving cognitive performancein schizophrenia. For example, positive allosteric modula- tors selective for GABAA receptors containing a2 subunits (eg, a GABAA a2-selective benzodiazepine) may improve The central noradrenergic system projects from the working memory function in schizophrenia.270 However, locus ceruleus to the prefrontal cortex where a drugs that directly activate a2-containing GABAA recep- ergic receptors appear to play an important role in tors independent of the presence of GABA may disrupt the cognitive functioning.256 Indeed, treatment with the critical synchronization of this circuit and impair working memory.269 In addition, activation of GABA 2-adrenergic receptor agonists, clonidine and guanfa- cine, has been shown to improve cognitive performance containing other subunits (eg, a1 or a5), such as by cur- without exacerbating positive symptoms in small rently available benzodiazepines, may impair cognitive trials of patients with schizophrenia.257,258 In addition, function. Indeed, a recent study in healthy volunteers patients randomized to risperidone plus guanfacine showed that, contrary to lorazepam, a GABAA a2/a3 showed significant improvement on tasks of working subtype–selective partial agonist, TPA023, caused no memory and attention compared with patients receiving typical antipsychotics plus guanfacine.258 However, clo- As activation of GABAA receptors containing a5 sub- zapine and other atypicals have potent antagonist prop- units, such as by currently available benzodiazepines, may impair cognitive function and cause sedation, inhib- contribute to the atypicality of atypicals by preferen- itors of these receptors have been hypothesized to en- tially enhancing dopaminergic transmission in the fron- hance cognition. Indeed, functionally selective inverse tal cortex over subcortical dopaminergic pathways.260 agonists at a5-containing GABAA receptors have been Indeed, combined treatment of a typical antipsychotic demonstrated to enhance performance in animal models of cognition,272–274 apparently without lowering the sei- nist, idazoxan, has been reported to produce a profile of zure threshold as seen with nonselective GABAA inverse antipsychotic activity similar to clozapine.261 Thus, as agonists.274,275 In addition, a5 subunit knockout mice demonstrate increased hippocampal activity due to the 2-adrenergic receptor activity may be important in de- veloping new drugs for schizophrenia that can improve release of tonic GABAergic inhibition.276 Thus, antago- cognition, balancing a2-adrenergic receptor activity to nists or inverse agonists at a5-containing GABAA recep- achieve both antipsychotic and procognitive efficacy tors may hold promise in the treatment of the cognitive Molecular Targets for Cognition in Schizophrenia schizophrenia and the theory that schizophrenia may in- The sigma (r) receptor was initially designated as a sub- volve a neurodegenerative process.298 Neurotrophic fac- type of opioid receptors277 but was later found to be a tors, such as brain-derived neurotrophic factor, may play distinct pharmacological entity due to lack of binding a role in neuronal and glial differentiation, proliferation, of the classical opiate receptor antagonists naloxone and regeneration and influence synaptic organization, and naltrexone.278 Indeed, when the r1 receptor was iso- neurotransmitter synthesis, and the maintenance of syn- lated and cloned, it was found to have no structural sim- aptic plasticity.299,300 Thus, strategies to enhance neuro- ilarity to the opioid receptors.279 The functions of these trophic factor action may be able to prevent progression receptors are poorly understood and endogenous ligands have yet to be identified, though it has been proposed that Altering neurotransmitter signaling by targeting intra- steroid hormones (eg, progesterone and testosterone), cellular signaling cascades has long been suggested to be drugs of abuse (eg, cocaine, heroin, PCP), and psychiatric a future approach to novel therapeutic agents.301 Though drugs (haloperidol, imipramine, and sertraline) may in- there has been concern about the feasibility of this ap- teract with r receptors.280,281 In addition, it is well docu- proach, lithium is a signal transduction modifier that mented that r1 receptor ligands increase the NMDA has been used safely for decades. Some targets being in- receptor response in the hippocampus,282–284 suggesting vestigated include protein kinase C isoforms and glyco- a role in enhancing cognition. Indeed, r1 receptor ago- gen synthase kinase 3.302 In addition, subtype-selective nists can reverse the memory impairments induced by the phosphodiesterase (PDE) inhibitors, particularly at PDE10A, are actively being explored for the treatment of various symptom domains in schizophrenia.303 An- (DHEA) and allopregnanolone, have been implicated other interesting approach at the receptor level would in neuroprotection286–288 and enhancement of NMDA be developing ligands that differentially activate the var- receptor neurotransmission,287,289,290 possibly through ious signaling pathways mediated by a single receptor, interaction with r1 receptors,290 suggesting therapeutic a process termed ‘‘functional selectivity’’.304 Indeed, potential for enhancing cognition in schizophrenia. Con- functional selectivity has been described in serotonin, sistent with the enhancement of NMDA neurotransmis- opioid, dopamine, vasopressin, and adrenergic receptor sion, DHEA can enhance memory in rodents.291–294 In systems304 and may be initiated by different ligand-in- humans, a double-blind study of DHEA as an adjunct duced conformational states, as shown for the b2-adren- to antipsychotic treatment in chronic schizophrenic ergic receptor.305 Thus, the possibility of selecting or patients with prominent negative symptoms suggests designing novel ligands that differentially activate only some efficacy at improving negative symptoms, especially a subset of receptor functions is intriguing as an approach in women,295 though further studies are needed. Thus, to drug discovery that may optimize therapeutic action.
neurosteroids may have therapeutic potential for improv-ing the cognitive deficits observed in schizophrenia, though long-term treatment with steroids is problematic.
In addition, while the contribution of r receptor agonism Cognitive dysfunction is a major feature of schizophrenia to the actions of neurosteroids is not entirely known, that contributes significantly to the long-term functional highly selective r receptor agonists are needed and impairment that patients experience. While the past half- century of antipsychotic development has had a profoundeffect on the treatment of schizophrenia, the cognitivedeficits addressed. Therefore, it is critical to continue the pursuit of diverse molecular targets for discovering new pharma- There are a number of additional largely theoretical phar- cotherapeutic agents for the treatment of schizophrenia.
macotherapeutic approaches for the treatment of cogni- For the past 20 years, psychopharmacologic research in tion and schizophrenia. For example, significant progress schizophrenia has aimed for the development of new an- has been made in recent years on elucidating various sus- tipsychotic drugs with a more rapid onset of action, ceptibility genes in schizophrenia, including dysbindin, lower risk of side effects, and improved efficacy in the neuregulin 1, COMT, DISC1, and others.296 Interest- domains of negative and cognitive symptoms from a sin- ingly, many of these genes appear to be related to the con- gle compound. Currently, however, it seems unlikely that trol of synaptic plasticity and glutamate transmission a single drug will have the desired effect across all these (particularly NMDA receptor function) and thus may al- domains, and thus, optimal treatment of schizophrenia low for hypothesis-driven approaches for developing of will likely rely on individualized polypharmacy and aug- actual disease-modifying drugs for schizophrenia and mentation strategies. The ultimate goal, of course, will be cognitive disorders.297 Another strategy involves the the development of ‘‘cure therapeutics’’297 which will re- role of neurotrophic factors in the pathophysiology of quire significant advances in our understanding of the underlying pathophysiology of schizophrenia, highlight- 16. Purdon SE, Jones BD, Stip E, et al. Neuropsychological ing the need for continued basic research efforts at iden- change in early phase schizophrenia during 12 months of tifying and validating diverse and novel molecular treatment with olanzapine, risperidone, or haloperidol. TheCanadian Collaborative Group for research in schizophre- nia. Arch Gen Psychiatry. 2000;57:249–258.
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