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Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Eur Neuropsychopharmacol. 2008 November ; 18(11): 773–786. doi:10.1016/j.euroneuro.2008.06.005.
Glutamatergic Dysfunction in Schizophrenia: from basic
neuroscience to clinical psychopharmacology
Rodrigo D. Paz1,2, Sonia Tardito2, Marco Atzori3, and Kuei Y. Tseng4
1Departamento de Psiquiatría y Neurociencias, Universidad Diego Portales, Santiago, Chile
2Instituto Psiquiátrico José Horwitz Barak, Santiago, Chile 3University of Texas at Dallas, School for Behavioral and Brain Sciences, Richardson, Texas, USA 4Department of Cellular & Molecular Pharmacology, RFUMS/The Chicago Medical School, NorthChicago, Illinois, USA Abstract
The underlying cellular mechanisms leading to frontal cortical hypofunction (i.e., hypofrontality) inschizophrenia remain unclear. Both hypoactive and hyperreactive prefrontal cortical (PFC) stateshave been reported in schizophrenia patients. Recent proton magnetic resonance spectroscopy studiesrevealed that antipsychotic-naïve patients with first-psychotic episode exhibit a hyperactive PFC.
Conversely, PFC activity seems to be diminished in patients chronically exposed to conventionalantipsychotic treatments, an effect that could reflect the therapeutic action as well as some of theimpairing side effects induced by long-term blockade of dopamine transmission. In this review, wewill provide an evolving picture of the pathophysiology of schizophrenia moving from dopamine toa more glutamatergic-centered hypothesis. We will discuss how alternative antipsychotic strategiesmay emerge by using drugs that reduce excessive glutamatergic response without altering the balanceof synaptic and extrasynaptic normal glutamatergic neurotransmission. Preclinical studies indicatethat acamprosate, a FDA approved drug for relapse prevention in detoxified alcoholic patients,reduces the glutamatergic hyperactivity triggered by ethanol withdrawal without depressing normalglutamatergic transmission. Whether this effect is mediated by a direct modulation of NMDAreceptors or by antagonism of metabotropic glutamate receptor remains to be determined. Wehypothesize that drugs with similar pharmacological actions to acamprosate may provide a betterand safer approach to reverse psychotic symptoms and cognitive deficits without altering the balance of excitation and inhibition of the corticolimbic dopamine-PFC system. It is predicted thatschizophrenia patients treated with acamprosate-like compounds will not exhibit progressive corticalatrophy associated with the anti-dopaminergic effect of classical antipsychotic exposure.
Keywords
schizophrenia; antipsychotic drugs; adolescence; NMDA; prefrontal cortex; dopamine; GABA;psychosis Corresponding Author: Kuei Y. Tseng, MD & PhD, Department of Cellular and Molecular Pharmacology, RFUMS/The Chicago MedicalSchool, North Chicago, Illinois 60064, USA, Phone: (1) 847-578-8655; Fax: (1) 847-578-3268, kuei-yuan.tseng@rosalindfranklin.edu.
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New and Old Problems in the Treatment of Schizophrenia Symptoms
Since the serendipitous discovery of drugs with antipsychotic properties in the '50s prolonged hospitalizations were no longer necessary for most patients with schizophrenia (Beasley et al.,2006, Freedman, 2005, Meltzer et al., 1990, Wiersma et al., 2000). During the '60s, thediscovery of clozapine, an antipsychotic drug exempt from extra-pyramidal side effects,introduced significant improvements in the treatment of this disorder (Hippius, 1989). Later,the demonstration of the unique effectiveness of this drug in refractory psychotic symptomsrepresented another advance (Kane et al., 1988). However, the emergence of fatalagranulocytosis during the '70s, and the more recent awareness of metabolic side effects(Bustillo et al., 1996, Cohen et al., 1990, Henderson et al., 2000, Lamberti et al., 2006) as wellas potentially lethal cases of pancreatitis, myocarditis and polyserositis (Killian et al., 1999,La Grenade et al., 2001, Merrill et al., 2006, Schonfeldt-Lecuona and Connemann, 2002,Wehmeier et al., 2003) associated with chronic exposure to clozapine, fueled the search forclozapine-like drugs not associated with life-threatening side effects. Pursuing this goal, severalnew antipsychotic drugs have been developed during the last decades. A reduced incidence ofextra-pyramidal side effects without inducing agranulocytosis has been demonstrated inpatients treated with second-generation drugs (Freedman, 2005, Gardner et al., 2005).
However, none of these so-called second-generation antipsychotics have achieved similarefficacy to clozapine (Azorin et al., 2001, Breier et al., 1999, Chakos et al., 2001, Conley et al., 1999, Davis et al., 2003, McEvoy et al., 2006, Shaw et al., 2006). More importantly,increased weight gain, hypercholesterolemia, diabetes and hyperprolactinemia still representserious side effects associated with chronic exposure to some of these compounds (Kapur etal., 2002, Volavka et al., 2004).
Besides the side effects, current available antipsychotic drugs have shown very limited impacton another core feature of schizophrenia, that is, cognitive and emotional impairments(Carpenter and Gold, 2002, Gardner et al., 2005, Keefe et al., 2006a, Keefe et al., 2006b,Mishara and Goldberg, 2004, Rosenheck et al., 2006). In fact, cognitive deficits are betterpredictor of the degree of social disability in patients with schizophrenia than the residualpsychotic symptoms (Gold et al., 2002, Green et al., 2000, Green et al., 2002, Hyman andFenton, 2003, Milev et al., 2005, Rosenheck et al., 2006). Likewise, emotional deficits haveemerged as another important predictor of disability in these patients (Milev et al., 2005). Thus,the lack of effectiveness of first and second generation antipsychotic drugs on cognitive andemotional deficits in schizophrenia may explain why the long-term prognosis in this psychiatricdisorder remains unsatisfactory (Hegarty et al., 1994, Malla and Payne, 2005, Wiersma et al.,2000).
Here, we will review recent evidence supporting an evolving picture of the pathophysiologyof schizophrenia moving from dopamine (DA) to a more glutamatergic-centered hypothesis.
We will first summarize the limitations of currently available antipsychotic drugs and presentevidence indicative of a hyperglutamatergic prefrontal cortex (PFC) underlying psychoticsymptoms in schizophrenia. Alternative notions from simple hypofrontality to a more complexdevelopmental dysregulation of prefrontal functioning will be introduced, in particular whetherthe glutamatergic hypothesis may be best framed as hypo- vs. hyperglutamatergic state. Next,we will discuss how partial NMDA receptor agonists and metabotropic glutamate receptor 5(mGluR5) antagonists (e.g. acamprosate) may be more effective in treating cognitive deficitsassociated to schizophrenia by restoring the balance of PFC glutamatergic function. Lastly, wewill propose a coherent hypothesis predicting the utility of acamprosate-like compounds asneuroprotective interventions in at-risk adolescents with cognitive and emotional impairmentsor sub-threshold psychotic symptoms.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Antipsychotic Drugs and Cognitive Symptoms in Schizophrenia
It is well known that current available antipsychotic drugs have limited effect in treating cognitive and emotional impairments in schizophrenia. In fact, cognitive deficits seem to beassociated with severe reduction in PFC volume in patients treated with haloperidol (Liebermanet al., 2005b), and the initial cognitive improvement observed after olanzapine (10-20 mg/day)and haloperidol (2-20 mg/day) treatment became no longer apparent after 1 year of drugexposure when detectable reductions in PFC volume emerge (Keefe et al., 2006a, Keefe et al.,2006b, Lieberman et al., 2005a). Similar PFC reductions in gray and white matter were foundafter 2 years of olanzapine or haloperidol exposure (Dorph-Petersen et al., 2005). Thus, thelack of cognitive improvement could be due to the anatomical and cellular alterations inducedby prolonged antipsychotic exposure as these changes seem to be positively correlated withthe cumulative doses of antipsychotic exposure (Cahn et al., 2002, Gur et al., 1998).
The mechanisms underlying the anatomical and molecular changes observed after chronicexposure to antipsychotics have yet to be identified. Evidences indicate that thesepathophysiological changes could be due to downregulation of neurotrophic factors inducedby the anti-DA effect of antipsychotic drugs, in particular by interfering signaling pathwaysunderlying D1 receptor activation. Although it is well established that first and secondgeneration antipsychotic drugs exert anti-DA effects, mainly by targeting D2 over D1 receptors(Creese et al., 1976, Seeman and Lee, 1975), prolonged blockade of D2 receptors can also lead to decreased expression of PFC D1 receptors (Castner et al., 2000, Lidow et al., 1997, Lidowand Goldman-Rakic, 1994). Consequently, chronic exposure to antipsychotic drugs mayproduce neuronal atrophy in DA-innervated brain areas by disrupting D1-dependent trophicsignaling (i.e., protein kinase A -PKA-) on growth and maintenance of new dendritic spines(Lisman and Grace, 2005). Indeed, D1 receptor activation increases surface expression ofAMPA receptor subunits in cortical neurons through a PKA-dependent mechanism (Smith etal., 2005, Sun et al., 2005), and alter the strength of synaptic communication induced by long-term potentiation (LTP) (Malenka, 2003), a cellular mechanism for learning and memory(Miles et al., 2005). Similarly, PKA activation facilitate the insertion of brain derivedneurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB) into the dendritic spines (Ji etal., 2005), and favors the arrangement of new dendritic spines (Tyler and Pozzo-Miller,2001). Therefore, D1-mediated PKA signaling may promote the formation of new dendriticspines and synaptic contacts during learning and memory (Jay, 2003, Lisman and Grace,2005), and disruption of D1 receptor-dependent neurotrophic signaling could explain some ofthe cellular and synaptic alterations observed after prolonged exposure to antipsychotic drugs(Konopaske et al., 2007): BDNF protein and mRNA levels were reduced in animals chronicallyexposed to haloperidol (Angelucci et al., 2000, Bai et al., 2003, Chlan-Fourney et al., 2002, Lipska et al., 2001, Pillai et al., 2006b), while downregulation of TrkB receptors in the PFCwas correlated with the duration and doses of antipsychotic treatment in schizophrenia patients(Weickert et al., 2005). Overall, these results indicate that first and second generationantipsychotic drugs may alter cortical levels of neurotrophic factors by antagonizing DAsignaling.
On the other hand, it has been proposed that the progressive cortical atrophy observed inschizophrenia patients with first psychotic episode could be triggered by psychosis itself(Lieberman, 1999, Lieberman et al., 2001, Lieberman et al., 2005b), whereas the delayedanatomical changes found in olanzapine-treated patients reflect a pro-neurotrophic effect thatcounter-balance the effect of first psychotic episode-induced neurotoxicity (Lieberman et al.,2005a, Lieberman et al., 2005b). However, neuropathological and gene expression studiesaimed to support the existence of first psychosis-induced neurotoxicity have yielded negativeresults (Benes et al., 2006, Benes et al., 2003, Damadzic et al., 2001, Harrison, 1999). Somestudies found reduction of BDNF expression (Lipska et al., 2001) whereas no change (Pillai Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
et al., 2006a) or even increased levels of BDNF were observed after chronic exposure toolanzapine and clozapine (Bai et al., 2003). A likely explanation for these contrasting results may be the duration of antipsychotic exposure. For example, it is well known that acuteadministration of second-generation antipsychotic drugs increases DA release in the medialPFC (Diaz-Mataix et al., 2005, Ichikawa et al., 2002, Li et al., 2005, Li et al., 2004, Li et al.,2003), an effect that could potentially lead to higher levels of BDNF (Bai et al., 2003). Incontrast, 180 days treatment with olanzapine showed no major effects on BDNF protein levels,but decreased significantly the activity and the levels of the neuroprotective enzymemanganese-superoxide dismutase in the cortex (Pillai et al., 2006a, Pillai et al., 2006b).
Similarly, a reduction of cortical gray and white matter was observed after two years ofolanzapine treatment in non-human primates (Dorph-Petersen et al., 2005). Interestingly,similar anatomical changes in the PFC were observed after twelve but not six-month exposureto olanzapine in schizophrenia patients exhibiting first psychotic episode (Lieberman et al.,2005b). Taken together, these findings suggest that prolonged treatments with second-generation antipsychotic drugs may alter PFC structure and function. Consistent with thishypothesis, a progressive decline in cognitive performance in a group of 80 schizophreniapatients (many of them treated with olanzapine or clozapine) was observed only after a two-year period of antipsychotic exposure (Andreasen et al., 2005). Studies exploring whetherprolonged exposure to second generation antipsychotic drugs increase DA release in the PFCmay shed some light on the mechanisms underlying the delayed cortical atrophy and cognitive deterioration associated with chronic exposure to antipsychotics. New therapeutic strategieswith better neuroprotective and neurocognitive profiles need to be examined, particularly infirst psychotic episode patients.
New Hypothesis for Addressing New Problems
Growing evidence indicates that abnormalities in glutamatergic neurotransmission mayunderlie some of the core psychopathological phenomena observed in schizophrenia (Harrisonand Weinberger, 2005). The glutamatergic hypothesis of schizophrenia was originally basedupon clinical observations of chronic abusers of the NMDA receptor antagonist phencyclidine(PCP). Similar to the symptoms observed in schizophrenia, PCP exposure elicits thoughtdisorder, emotional blunting, working memory disturbances and auditory hallucinations (Javittand Zukin, 1991, Luby et al., 1959). The observation that acute administration of anotherNMDA receptor antagonist, that is, sub-anesthetic doses of ketamine, induces similarpsychopathological effects in healthy volunteers (Adler et al., 1999, Krystal et al., 1994,Malhotra et al., 1996) supported the hypothesis that hypofunctional NMDA receptors may playa critical role in the pathophysiology of schizophrenia. Consequently, anti-DA drugs combinedwith agents that enhance NMDA function might ameliorate the residual cognitive, emotional and psychotic symptoms in schizophrenia (Goff and Coyle, 2001, Goff et al., 1999). However,a recent multicentric study failed to provide evidence in favor of this therapeutic intervention(Carpenter and Thaker, 2007).
A re-formulation of the glutamatergic hypothesis of schizophrenia has emerged. According tothis new paradigm, hyperactive glutamatergic neurons in several brain regions including thePFC may underlie the psychotic, cognitive and emotional manifestations in schizophrenia(Krystal et al., 2003, Moghaddam, 2003). Several pieces of converging evidence havecontributed to establish this reformulation: 1) Microdialysis studies showing that glutamatelevels are increased in the striatum (Bustos et al., 1992) and PFC (Moghaddam et al., 1997) ofanimals acutely treated with psychotomimetic doses of NMDA antagonists; 2) Behavioralstudies showing that hyperlocomotion and working memory impairments induced by PCP arecorrelated with increased glutamate levels in the PFC (Adams and Moghaddam, 1998); 3)Pharmacological studies showing that glutamate release inhibitors such as lamotrigine (Anandet al., 2000) and mGluR 2 agonists (Moghaddam and Adams, 1998) ameliorate the cognitive Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
and behavioral abnormalities induced by acute exposure to psychotomimetic doses of NMDAantagonists; 4) In vivo electrophysiological recordings in freely moving animals revealing that acute administration of NMDA antagonists is associated with PFC pyramidal neuronsexcitation (Jackson et al., 2004), an effect that could be triggered by an increased tonicexcitatory inputs from the ventral hippocampus (Jodo et al., 2005); 5) In vitroelectrophysiological studies showing that hippocampal GABAergic interneurons that controlpyramidal neuron firing are particularly sensitive to psychotomimetic doses of NMDAantagonists (Grunze et al., 1996); 6) Neuroimaging studies indicating that psychotic symptomsand cognitive abnormalities elicited by acute administration of ketamine in healthy volunteersconcur with an enhancement of PFC metabolic activity (Breier et al., 1997, Holcomb et al.,2005, Holcomb et al., 2001); 7) Proton magnetic resonance spectroscopy studies showing thatglutamine levels, an indicator of synaptic glutamate recycling activity (Rothman et al., 1999),are increased in the medial PFC of healthy volunteers acutely exposed to sub-anesthetic dosesof ketamine (Rowland et al., 2005), antipsychotic naïve first psychotic episode schizophreniapatients (Bartha et al., 1997, Theberge et al., 2002), and adolescents at-risk of developingschizophrenia (Tibbo et al., 2004). Thus, despite binding at different receptors in dendriticspines, psychotomimetic drugs such as LSD, amphetamine and PCP may trigger signaltransduction pathways that converge to potentiate glutamatergic excitability via inhibition ofprotein phosphatase 1, an enzyme that normally downregulates excitatory synapses(Svenningsson et al., 2003). At the network level, psychotomimetic doses of NMDA antagonist may favor the balance of excitation over inhibition by blocking NMDA-dependent excitatoryinputs to GABAergic interneurons. Overall, these results indicate that a dysfunctionalenhancement of cortical excitatory transmission maybe the common synaptic effect ofpsychotomimetic drugs that induced schizophrenia-like symptoms.
How a primary dysregulation of glutamatergic neurotransmission may explain the fact that
most cases of schizophrenia emerge after puberty?
Electrophysiological recordings of PFC pyramidal neurons at different maturational stageshave revealed that DA-glutamate interactions in the PFC mature after puberty (Tseng andO'Donnell, 2004, Tseng and O'Donnell, 2005). Therefore, a cortical disruption of NMDAfunction may contribute to establish the pathophysiological changes observed in schizophreniaby altering the acquisition of mature DA responses in the PFC. For example, glutamatergicplateau depolarizations induced by co-activation of NMDA and D1 receptors isdevelopmentally regulated in a manner that a D1-dependent enhancement of NMDA functionin the PFC can be observed only in post-pubertal, but not pre-pubertal animals (Tseng andO'Donnell, 2005). This is consistent with previous studies showing a delayed acquisition ofadult levels of DA receptors (Leslie et al., 1991, Tarazi et al., 1999) and NMDA receptorsubunits (Monyer et al., 1994, Williams et al., 1993) around puberty. Furthermore, the expression of BDNF mRNA, which is tightly dependent on the activation of intra-synapticNMDA receptors (Hardingham et al., 2002), reaches its maximum level in the PFC during lateadolescence and young adulthood (Webster et al., 2002). Thus, subtle changes in glutamatergicexcitability determined by genetic and environmental factors may drive some of the mildcognitive, emotional and motor abnormalities observed in pre-psychotic children andadolescents (Lewis and Levitt, 2002, Lewis and Murray, 1987, Murray and Waddington,1990, Weinberger, 1987). These changes may remain relatively silent until the acquisition ofmature cognitive abilities dependent on D1-NMDA interactions that emerge around puberty(Tseng and O'Donnell, 2005). A developmental disruption of either or both the glutamatergicand the DA systems may therefore lead to the cognitive and emotional manifestations ofprodromal schizophrenia (Lencz et al., 2006, Reichenberg et al., 2005, Weiser et al., 2001).
Without treatment, post-pubertal hyperglutamatergic states may escalate until full psychoticepisodes emerge during late adolescence and early adulthood.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
The Glutamatergic Hypothesis for Psychosis: addressing the objections
Could the hyperglutamatergic neurotransmission, exacerbated by an abnormal D1-NMDA
co-activation during late adolescence underlie the core of early pathophysiological events
in schizophrenia?
This hypothesis may appear at odds by the fact that antipsychotic drugs have been shown totarget mainly D2 over D1 receptors (Tauscher et al., 2004). If an exaggerated PFC D1-NMDA-dependent excitation plays a role in psychosis, it may seem unlikely that D2 antagonists wouldexert any antipsychotic effects. However, it is well known that prolonged exposure to D2antagonists are typically associated with a series of changes including downregulation of PFCD1 receptors (Castner et al., 2000, Lidow et al., 1997, Lidow and Goldman-Rakic, 1994) andDA cell firing (Bai et al., 2003, Boye and Rompre, 2000, Bunney and Grace, 1978, Di Giovanniet al., 1998, Grace et al., 1997, Moore et al., 1998), which in turn may decrease DA synthesis(Grunder et al., 2003) and impair prefrontal D1-dependent functioning. On the other hand, ithas been documented that some of the behavioral effects of DA are dependent on co-activationof D1 and D2 receptors within the cortico-basal ganglia loop (Kita et al., 1999, Waszczak etal., 2002). Both D1 and D2 DA receptors are co-expressed in single striatal neurons and theirco-activation can lead to calcium release from internal stores (Aizman et al., 2000, Lee et al.,2004, So et al., 2005) and increase neuronal activity (Hopf et al., 2003). It is possible that D2antagonists prevent D1 mediated potentiation of NMDA response within the PFC by decreasing the D2-dependent calcium release from internal stores. Although this hypothesis awaitsconfirmation in cortical neurons, it seems likely that chronic blockade of D2 receptors couldultimately compromise cognitive performance by disrupting PFC D1-dependent signaling.
Why selective D1 antagonists failed to elicit significant therapeutic effects in schizophrenia?
Several factors may explain the lack of effectiveness of selective D1 antagonists in treatingsymptoms associated to schizophrenia (de Beaurepaire et al., 1995, Den Boer et al., 1995,Karlsson et al., 1995). First, the therapeutic effects of D1 antagonists were initially tested inpatients exposed to prolonged antipsychotic drugs treatment, a stage where therehyperglutamatergic state may not longer present in the PFC (Bartha et al., 1997, Theberge etal., 2002, Tibbo et al., 2004). Secondly, it has been suggested that a proper balance of PFC D1receptor activation (i.e., invert U curve) is required for supporting optimal working memoryperformance (Arnsten and Li, 2005). Several studies have also highlighted the need of DA-glutamate co-activation for a number of prefrontal functions including appetitive instrumentallearning, memory retrieval and enhancement of hippocampal-PFC synaptic plasticity (Baldwinet al., 2002, Gurden et al., 1999, Jay, 2003). Thus, potent D1 antagonists may not only reducethe hyperglutamatergic state but also impair PFC functioning in schizophrenia. Two trials using full D1 antagonists have to be aborted as result of the emergence of severe psychosisexacerbation (de Beaurepaire et al., 1995, Karlsson et al., 1995).
Finally, it is not clear whether cognitive and emotional deterioration putatively driven bychronic hypoglutamatergic states are the result of prolonged antipsychotic exposure sincesimilar deficits were reported in schizophrenia subjects before the introduction of anti-DAdrugs (Kraepelin, 1919; Bleuler, 1911). It has been documented that chronic exposure to lowdoses of NMDA antagonist significantly decrease PFC DA and glutamate turnover (Jentschand Roth, 1999, Kondziella et al., 2005) and elicit PFC-related behavioral deficits resemblingthe cognitive deterioration observed in chronic stages of schizophrenia (Jentsch et al., 1997,Jentsch and Roth, 1999). Taken together, these findings suggest that repetitive episodes ofhyperglutamatergic activity may trigger compensatory mechanisms that would in turndownregulate PFC excitatory transmission. Thus, even in the absence of D2 antagonists, ahypoglutamatergic PFC may emerge resulting from repetitive untreated hyperglutamatergicstate as seen after chronic exposure to PCP.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
In summary, it is possible that the emergence of an abnormal PFC D1-NMDA co-activationduring late adolescence could exacerbate the hyperglutamatergic state that underlies the early pathophysiological events in schizophrenia. If the model proposed here capture at least part ofwhat is really occurring in early stages of schizophrenia, we predict that the earlier theintroduction of non-DA therapeutic interventions, the higher the probability of preventingcompensatory changes associated with a hypoactive PFC.
Cellular Mechanisms Underlying the Hyperglutamatergic State
Several DA-dependent and DA-independent factors could contribute to elicit the hyperactiveNMDA state in schizophrenia. At cellular level, an increase expression of calcyon (Koh et al.,2003), a D1 receptor interacting protein that allows calcium release from internal stores(Bergson et al., 2003), may potentiate NMDA function in a manner independent from D2receptor activation. Similarly, reduction of calcineurin levels (Eastwood et al., 2005, Gerberet al., 2003), a phosphatase that normally reduces the excitability of NMDA receptors (Rycroftand Gibb, 2004, Smith et al., 2006), may also enhance NMDA function and promote workingmemory deficits in response to low doses of the NMDA antagonist MK801 (Miyakawa et al.,2003). Furthermore, a reduced expression of the RSG4 gene (Chowdari et al., 2002, Erdely etal., 2006, Prasad et al., 2005, Saugstad et al., 1998), which encodes a protein product thatnormally decreases the activation of mGluR5, may result in over-activation of NMDAreceptors. This change at mGluR5 function might ultimately increase PFC pyramidal neurons bursting activity through an NMDA-dependent mechanism (Homayoun et al., 2004). Finally,a recent study has identified a genetic defect affecting the expression of the phosphodiesterase4B gene (PDE4B) in schizophrenia and mood disorders. This gene product plays a critical rolein maintaining the normal D1-dependent protein kinase A signal transduction pathway. Moreimportantly, it was found that the PDE4B enzyme interacts with the disrupted in schizophrenia1 (DISC 1) gene in a manner that PDE4B can be released from DISC 1 when the dendriticlevels of cyclic adenosine monophosphate (cAMP) are elevated (Millar et al., 2005). Thus,abnormalities in the expression or activity of different gene products such as calcyon,calcineurin, PDE4B and DISC 1 may lead to hyper-excitable signal transduction pathwaysdependent on D1-NMDA receptor activation.
Disruption of GABAergic interneurons function may also contribute to initiate and sustain ahyperglutamatergic state in schizophrenia. PFC GABAergic interneurons play an importantrole in determining the responses of pyramidal neurons to glutamatergic and DA inputs (Tsenget al., 2006b, Tseng and O'Donnell, 2004, Tseng and O'Donnell, 2007a, Tseng and O'Donnell,2007b) and functional disruption of this selective neuronal population could ultimately lead tothe altered cognitive performances observed in schizophrenia (Lewis et al., 2005). Because DA-dependent attenuation of PFC NMDA responses involves activation of local GABAergicinterneurons (Tseng and O'Donnell, 2004), a reduction of this inhibitory tone may alsocontribute to trigger and sustain the hyperglutamatergic state in the PFC. Although an overallenhancement of PFC activity may appear at odds with the traditional concept of hypofrontality(Manoach, 2003), recent studies conducted in a developmental animal model that exhibitscortical deficits resembling to those observed in schizophrenia indicate that the hypofrontalstate could be associated with an hyperactive PFC. The characteristic post-pubertal emergenceof PFC glutamatergic hyperactivity (O'Donnell et al., 2002, Tseng et al., 2007) andhyperreactive PFC metabolic response to mesocortical stimulation (Tseng et al., 2006a) arecorrelated with a selective down regulation of PFC glutamate decarboxylase-67 mRNA, aneuronal marker for GABA interneurons (Lipska et al., 2003). Furthermore, a postpubertaldisruption of D2 receptor function that normally regulate PFC excitatory responses throughseveral pre- and postsynaptic mechanisms (Tseng and O'Donnell, 2004, Tseng and O'Donnell,2007a) combined with an abnormal response to D1 activation may also serve to increasepyramidal neurons excitability to NMDA (Tseng et al., 2007) and yield the concurrent hyper- Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
reactive and hypofunctional state in the PFC (Tseng et al., 2006a). Finally, it is also possiblethat other monoamines may potentiate this abnormal enhancement of NMDA function, particularly the cortical norepinephrine system. Stress-dependent increases of norepinephrinerelease sustaining the hyperactive NMDA state through activation of α1 adrenergic receptorsand upregulation of postsynaptic protein kinase C signaling pathways in the PFC (Arnsten,2004) may underlie the hyperreactive response to stress observed in schizophrenia.
In summary, cortical deficits in schizophrenia (i.e., hypofrontality) could be thereforecompounded by a hyperglutamatergic PFC state elicited by a reduction of PFC GABAergicfunction concurrent with a disruption of D2 modulation and an abnormal potentiation of D1and NMDA-mediated responses. These two pathophysiological conditions are not mutuallyexclusive and may not be restricted to the PFC since markers of increased glutamatergic activitydependent on NMDA receptors concurs with those indicative of decreased GABAergicfunction such as of GAD-67, GAD-65 and GAT1 in the cerebellar cortex of patients withschizophrenia (Paz et al., 2006).
Searching for New Psychopharmacological Targets to Restore the Balance
of Glutamatergic Neurotransmission: a lesson from acamprosate
Acamprosate is a derivative of the amino acid taurine and despite its low intestinal absorption, it has been used for more than two decades in Europe to prevent relapse in alcoholic patients(Buonopane and Petrakis, 2005, Room et al., 2005, Williams, 2005). Recently, the FDAapproved the use of acamprosate for detoxified alcohol-dependent patients in USA. Althoughits mechanism of action has not been completely identified, preclinical studies suggest thatacamprosate normalizes glutamate release and NMDA receptors function without altering thenormal glutamatergic neurotransmission (De Witte et al., 2005). Several cellular mechanismsmay account for the therapeutic effect of acamprosate, particularly by interfering mGluR5-dependent regulation of glutamate release (De Witte et al., 2005). Metabotropic GluR5 is anexcitatory G-protein coupled receptor located at both pre- and postsynaptic sites ofglutamatergic synapses as well as in glia and astrocytes (Swanson et al., 2005). Activation ofpresynaptic mGluR5 facilitates synaptic glutamate release whereas postsynaptic mGluR5increase neuronal excitability by facilitating NMDA currents. Consequently, a reduction of thehyperglutamatergic PFC state could be achieved with acamprosate by attenuating the excitatoryeffect of mGluR5 on presynaptic glutamate release and by decreasing NMDA-dependentpostsynaptic excitability. On the other hand, mGluR5 also regulates non-synaptic release ofglutamate from glia and astrocytes via stimulation of the cystine-glutamate antiporter (Xc-)(Melendez et al., 2005, Moran et al., 2005). The Xc- is a non-vesicular transporter that mediatessodium-independent exchange of one intracellular glutamate for one extracellular molecule of cystine, and is responsible for around 50 to 70 % of basal extracellular glutamate in the nucleusaccumbens (Baker et al., 2002), but not in the PFC (Melendez et al., 2005). In the PFC, however,Xc- stimulation increases the concentration of non-synaptic, extracellular glutamate, andreduces excitatory synaptic transmission resulting from activation of the inhibitory presynapticmGluR2/3 (Moran et al., 2005). Accordingly, acamprosate would prevent activation of the Xc-antiporter by antagonizing mGluR5, which in turn would reduce the non-synaptic extracellularglutamate levels and remove the presynaptic mGluR2/3-dependent inhibitory tone atglutamatergic synapses. Removing the mGluR2/3-dependent inhibitory tone on glutamaterelease might actually contribute to balance the decrease in glutamatergic synaptic transmissioninduced by presynaptic mGluR5 blockade. It is predicted that by acting on both synaptic andnon-synaptic mechanisms underlying glutamate release and its interactions with postsynapticNMDA receptors, acamprosate-like compounds may restore PFC hyperglutamatergic statewithout altering the balance of excitatory neurotransmission Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Acamprosate also binds the spermidine site of NMDA receptors (Mayer et al., 2002, Naassilaet al., 1998) and it is thought to exert a partial agonistic effect acting as an agonist or antagonist depending on the activity of NMDA receptors. For example, acamprosate potentiates theexcitatory action induced by low concentration of NMDA and reduced the excitatory effectelicited by higher concentrations of NMDA (Pierrefiche et al., 2004). Accordingly, studies inhyperglutamatergic mutant mice (a rodent model of increased alcohol consumption) revealedthat acamprosate normalize glutamate levels and ethanol intake without affecting glutamatelevels of control animals (Spanagel et al., 2005). A similar effect was observed in thehippocampus of ethanol-withdrawn rats treated with acamprosate as compared to controlanimals (Room et al., 2005). Because repetitive exposure to ethanol and withdrawal increasesglutamatergic transmission and glutamate release (De Witte, 2004, Krystal et al., 2003), theincreased glutamate would reach the extrasynaptic space, which in turn would stimulate moremGluR5 receptors and cause even more glutamate release and abnormal NMDA activation(De Witte et al., 2005). Therefore, acamprosate may effectively block this vicious cycle bynormalizing and restoring the balance of glutamatergic neurotransmission across several brainregions through its combined action on mGluR5 and NMDA receptor functions. Furthermore,the increased ethanol intake observed in the hyperglutamatergic mice (Spanagel et al., 2005)raises the intriguing possibility that similar exacerbated glutamatergic condition may bedriving, at least in part, the increased prevalence of ethanol abuse and dependence observed inschizophrenia. Interestingly, glutamate-dependent neurotoxicity induced by acute exposure to intermediate doses of NMDA antagonists could be prevented by ethanol exposure in rats(Farber et al., 2004).
Overall, it is tempting to speculate that the modulatory action of compounds that block mGluR5and exert a partial agonistic effect on NMDA receptors (e.g., acamprosate-like compounds andpossibly others) could provide a much better result in restoring altered glutamatergicneurotransmission than that produced by NMDA agonists and antagonists, and that obtainedwith D2 antagonists, in particular during early stages of the disorder.
Advantages of Using Acamprosate-like Drugs in Prodromal Stages of
Schizophrenia
It has been proposed that anti-DA treatments during the early stages of first-episode psychosesmay be effective to prevent cognitive and emotional decline in schizophrenia (Lieberman,1999, Wyatt, 1991). However, recent studies indicate that this strategy does not truly improvethe cognitive and emotional outcomes(Ho et al., 2003, Hoff et al., 2000, Marshall et al.,2005, Perkins et al., 2005, Rund et al., 2004), perhaps because cognitive deficits inschizophrenia occurs during late adolescence, before the emergence of psychotic episodes (Perkins et al., 2005). In fact, several retrospective studies have found that cognitive andemotional deterioration in a subgroup of schizophrenia patients become evident when post-pubertal social and cognitive performances are compared with those exhibited in prepubertalages (Ang and Tan, 2004, Cosway et al., 2000, Fuller et al., 2002, Rabinowitz et al., 2002,Reichenberg et al., 2005, van Oel et al., 2002). Although limited by their retrospective nature,these studies are consistent with the idea that profound changes occurring in the adolescentbrain make this neural development period vulnerable. Accelerated pruning of redundantconnections in the PFC occurs during this developmental stage (Bourgeois et al., 1994,Huttenlocher, 1979, Huttenlocher and Dabholkar, 1997, Zecevic et al., 1989, Zecevic andRakic, 1991), while the myelination of axons projecting from the PFC is particularly intenseduring adolescence and young adulthood (Giedd et al., 1999, Gogtay et al., 2004, Jernigan etal., 1991, Paus et al., 1999, Sowell et al., 2003, Sowell et al., 1999, Toga et al., 2006). Sincethese events are probably dependent on plastic changes affecting the glutamatergic (Monyeret al., 1994, Williams et al., 1993) and the DA systems (Leslie et al., 1991, Tarazi et al.,1999), it is not surprising that PFC pyramidal neuron response to DA acquire a mature profile Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
at early postpubertal stages of neural development (Tarazi et al., 1999, Tseng et al., 2006a,Tseng and O'Donnell, 2005, Tseng and O'Donnell, 2007a, Tseng and O'Donnell, 2007b). A similar delayed acquisition of mature responses to DA has been recently observed in PFCinterneurons (Tseng and O'Donnell, 2007a, Tseng and O'Donnell, 2007b). All theseinteractions will ultimately determine the normal balance of excitation and inhibition that isneeded for optimal cognitive performances including those dependent on PFC functioningduring adulthood. Thus, several abnormalities at cellular and network levels compromisingboth glutamatergic and GABAergic systems may produce dramatic effects during criticalperiods of neural development that could potentially lead to permanent loss of synapticconnections resulting in cognitive and emotional alterations in adulthood. Consequently, acuteexposure to low doses of NMDA antagonists induces psychotic symptoms and cognitivedysfunctions in pubertal/postpubertal rather than prepubertal ages (Olney and Farber, 1995).
Modulation of glutamatergic neurotransmission within the mesocorticolimbic-PFC networkby drugs acting on metabotropic and NMDA glutamate receptors may allow a better controlof persistent hyperglutamatergic states that are not affected by D2 receptor blockade. In thisregard, it is appealing that clozapine binds D1 receptors with a higher affinity than D2 receptors(Chou et al., 2006, Tauscher et al., 2004). Therefore, clozapine may exert a more directinteraction with NMDA receptors than other antipsychotic drugs, in particular if thehyperglutamatergic state is exacerbated by an abnormal PFC D1-NMDA co-activation. In fact, the response to clozapine can be predicted by polymorphisms within the D1 receptor gene inschizophrenia subjects. Patients with the 2,2, but not with the 1,2 D1 genotype exhibiteddecrements in psychotic symptoms after clozapine treatment, a therapeutic effect associatedwith a reduction in PFC metabolism that was not observed in the 1,2 D1 group (Potkin et al.,2003). Furthermore, prolonged clozapine exposure (i.e., 21 days) decreased NMDA-dependentsynaptic function (i.e., LTP) (Gemperle and Olpe, 2004). Thus, the therapeutic effects ofclozapine in patients with refractory psychotic symptoms might be obtained by decreasing theabnormal PFC D1-NMDA-dependent excitation.
A narrow window of NMDA activation mediated by D1 receptors and α adrenergic receptorsis needed to maintain appropriate working memory performance. An excessive stimulation ofD1 receptors lead to cognitive dysfunction (Arnsten and Goldman-Rakic, 1998, Cai andArnsten, 1997, Zahrt et al., 1997) whereas insufficient recruitment of these receptors isassociated with working memory deficits (Castner et al., 2000, Sawaguchi and Goldman-Rakic,1994). Interestingly, a similar inverted U-shape response has been reported for noradrenergicmanipulations (Arnsten and Li, 2005). Therefore, drugs with anti-mGluR5 and partial NMDAagonist properties (e.g., acamprosate) might produce better outcomes in patients with severecognitive dysfunction. Along with this hypothesis, transgenic mice overexpressing D2 receptors in the striatum exhibit severe deficits in working memory-dependent tasks inassociation with increased D1 receptor responses in the PFC (Kellendonk et al., 2006).
Decreasing the expression of D2 receptors in the striatum failed to restore the increased PFCresponse. This suggests that blocking D2 receptors in the striatum does not prevent workingmemory impairments secondary to neurodevelopmentally-induced abnormalities of D1-NMDA interactions within the PFC. Thus, direct modulation of hyperactive NMDA receptorsby drugs like acamprosate may allow targeting microcircuits within the mesocortico-PFC thatare not accessible to conventional D2-based treatments.
Because suicide is a major cause of mortality in schizophrenia and a risk factor for youngadults, a note of caution should be mentioned concerning the use of acamprosate in alcoholicpatients with suicidal ideation and suicide attempts. Although infrequent, acamprosate seemsto induce a relatively higher risk of suicidal thoughts and attempted suicide (2.4 %) whencompared to placebo (0.8 %) (2005, Bouza et al., 2004, Chick et al., 2000, Sher, 2006a).
However, the incidence of completed suicide in patients receiving acamprosate (0.13 %) Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
resembled to that observed in the placebo group (0.10 %)). Because many of these suicidal-related events occurred in the context of alcohol dependence and relapse, the relationship betweenacamprosate and the emergence of suicidality remains unclear (Sher, 2006b).
Summary and Conclusions
Overall, it becomes clear that the vulnerability of the periadolescence brain to environmentallyand genetically driven events that could potentially disrupt the balance of excitation andinhibition in cortical circuits should be taken into consideration when planningpsychopharmacological treatments in at-risk adolescent patients exhibiting cognitive andemotional deterioration. Drugs with similar acamprosate-like profile on metabotropicglutamate (e.g., mGluR5) and NMDA receptors may provide a better and safer therapeuticstrategy for early stages schizophrenia as compared to risperidone (McGorry et al., 2002),olanzapine (McGlashan et al., 2006, McGlashan et al., 2003) or D-cycloserine (Buchanan etal., 2007). The development of drugs that restore the hyperglutamatergic state by virtue ofnormalizing the abnormal NMDA function without altering the balance of synaptic andextrasynaptic glutamatergic transmission may be useful for schizophrenia patients withpersistent and residual psychotic symptoms as well as cognitive and emotional deficits.
Acknowledgments
Supported by NIDCD 1R01-DC005986-01A1 and NARSAD foundation/Sidney Baer Trust (MA) and RFUMS-TheChicago Medical School Start-up Funds (KYT) References
Acamprosate campral for alcoholism. Med Lett Drugs Ther 2005;47:1–3. [PubMed: 15599336] Adams B, Moghaddam B. Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J Neurosci 1998;18:5545–54. [PubMed: 9651235] Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A. Comparison of ketamine- induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry1999;156:1646–9. [PubMed: 10518181] Aizman O, Brismar H, Uhlen P, Zettergren E, Levey AI, Forssberg H, Greengard P, Aperia A. Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons.
Nat Neurosci 2000;3:226–30. [PubMed: 10700253] Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000;57:270–6. [PubMed: 10711913] Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005;162:441–9.
[PubMed: 15741458] Ang YG, Tan HY. Academic deterioration prior to first episode schizophrenia in young Singaporean males. Psychiatry Res 2004;121:303–7. [PubMed: 14675749] Angelucci F, Mathe AA, Aloe L. Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res2000;60:783–94. [PubMed: 10861791] Arnsten AF. Adrenergic targets for the treatment of cognitive deficits in schizophrenia.
Psychopharmacology (Berl) 2004;174:25–31. [PubMed: 15205875] Arnsten AF, Goldman-Rakic PS. Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 1998;55:362–8. [PubMed:9554432] Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 2005;57:1377–84. [PubMed: 15950011] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, Bourdeix I. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.
Am J Psychiatry 2001;158:1305–13. [PubMed: 11481167] Bai O, Chlan-Fourney J, Bowen R, Keegan D, Li XM. Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003;71:127–31. [PubMed: 12478621] Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 2002;22:9134–41. [PubMed: 12388621] Baldwin AE, Sadeghian K, Kelley AE. Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex. J Neurosci 2002;22:1063–71. [PubMed: 11826135] Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L, Canaran G, Rylett RJ, Neufeld RW.
Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treatedschizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch GenPsychiatry 1997;54:959–65. [PubMed: 9337777] Beasley CM Jr, Sutton VK, Taylor CC, Sethuraman G, Dossenbach M, Naber D. Is quality of life among minimally symptomatic patients with schizophrenia better following withdrawal or continuation ofantipsychotic treatment? J Clin Psychopharmacol 2006;26:40–4. [PubMed: 16415704] Benes FM, Matzilevich D, Burke RE, Walsh J. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry 2006;11:241–51. [PubMed: 16288314] Benes FM, Walsh J, Bhattacharyya S, Sheth A, Berretta S. DNA fragmentation decreased in schizophrenia but not bipolar disorder. Arch Gen Psychiatry 2003;60:359–64. [PubMed: 12695312] Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS. Dopamine receptor-interacting proteins: the Ca (2+) connection in dopamine signaling. Trends Pharmacol Sci 2003;24:486–92. [PubMed:12967774] Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys.
Cereb Cortex 1994;4:78–96. [PubMed: 8180493] Bouza C, Angeles M, Munoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811–28. [PubMed:15200577] Boye SM, Rompre PP. Behavioral evidence of depolarization block of dopamine neurons after chronic treatment with haloperidol and clozapine. J Neurosci 2000;20:1229–39. [PubMed: 10648727] Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997;154:805–11. [PubMed: 9167508] Breier AF, Malhotra AK, Su TP, Pinals DA, Elman I, Adler CM, Lafargue RT, Clifton A, Pickar D.
Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects,and neuroendocrine response. Am J Psychiatry 1999;156:294–8. [PubMed: 9989566] Bleuler, E. Dementia Praecox or the Group of Schizophrenias. Zinkin, J., translator. New York, NY: International Universities Press; 1911. 1950.
Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, Mcmahon RP, Heresco-Levy U, Carpenter WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy ofglutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry2007;164:1593–602. [PubMed: 17898352] Bunney BS, Grace AA. Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity. Life Sci 1978;23:1715–27. [PubMed: 31529] Buonopane A, Petrakis IL. Pharmacotherapy of alcohol use disorders. Subst Use Misuse 2005;40:2001– Bustillo JR, Buchanan RW, Irish D, Breier A. Differential effect of clozapine on weight: a controlled study. Am J Psychiatry 1996;153:817–9. [PubMed: 8633697] Bustos G, Abarca J, Forray MI, Gysling K, Bradberry CW, Roth RH. Regulation of excitatory amino acid release by N-methyl-D-aspartate receptors in rat striatum: in vivo microdialysis studies. BrainRes 1992;585:105–15. [PubMed: 1355000] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Cahn W, Hulshoff Pol HE, Lems EB, Van Haren NE, Schnack HG, Van Der Linden JA, Schothorst PF, Van Engeland H, Kahn RS. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;59:1002–10. [PubMed: 12418933] Cai JX, Arnsten AF. Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 1997;283:183–9. [PubMed:9336323] CAMPRAK. (acamprosate calcium) delayed-release tablets [Product information]. St. Louis, Mo.: Forest Carpenter WT, Gold JM. Another view of therapy for cognition in schizophrenia. Biol Psychiatry Carpenter WT, Thaker GK. Evidence-based therapeutics--introducing the Cochrane corner. Schizophr Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 2000;287:2020–2. [PubMed:10720329] Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis ofrandomized trials. Am J Psychiatry 2001;158:518–26. [PubMed: 11282684] Chick J, Howlett H, Morgan MY, Ritson B. United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawalfrom alcohol. Alcohol Alcohol 2000;35:176–87. [PubMed: 10787394] Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM. Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 2002;954:11–20. [PubMed:12393228] Chou YH, Halldin C, Farde L. Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study. Psychopharmacology (Berl) 2006;185:29–35. [PubMed: 16395606] Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SN, T BK, Ferrell RE, Middleton FA, Devlin B, Levitt P, Lewis DA, Nimgaonkar VL. Association and linkage analyses ofRGS4 polymorphisms in schizophrenia. Hum Mol Genet 2002;11:1373–80. [PubMed: 12023979] Cohen S, Chiles J, Macnaughton A. Weight gain associated with clozapine. Am J Psychiatry Conley RR, Tamminga CA, Kelly DL, Richardson CM. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry 1999;46:73–7. [PubMed:10394475] Cosway R, Byrne M, Clafferty R, Hodges A, Grant E, Abukmeil SS, Lawrie SM, Miller P, Johnstone EC. Neuropsychological change in young people at high risk for schizophrenia: results from the firsttwo neuropsychological assessments of the Edinburgh High Risk Study. Psychol Med 2000;30:1111–21. [PubMed: 12027047] Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976;192:481–3. [PubMed: 3854] Damadzic R, Bigelow LB, Krimer LS, Goldenson DA, Saunders RC, Kleinman JE, Herman MM. A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia,bipolar disorder and major depression: absence of significant astrocytosis. Brain Res Bull2001;55:611–8. [PubMed: 11576757] Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553–64. [PubMed: 12796218] De Beaurepaire R, Labelle A, Naber D, Jones BD, Barnes TR. An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states. Psychopharmacology (Berl) 1995;121:323–7. [PubMed:8584613] De Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict Behav 2004;29:1325–39. [PubMed: 15345268] De Witte P, Littleton J, Parot P, Koob G. Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 2005;19:517–37. [PubMed:15963001] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Den Boer JA, Van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG, Burrows GD, Srivastava ON. Differential effects of the D1-DA receptor antagonist SCH39166 on positiveand negative symptoms of schizophrenia. Psychopharmacology (Berl) 1995;121:317–22. [PubMed: Di Giovanni G, Di Mascio M, Di Matteo V, Esposito E. Effects of acute and repeated administration of amisulpride, a dopamine D2/D3 receptor antagonist, on the electrical activity of midbraindopaminergic neurons. J Pharmacol Exp Ther 1998;287:51–7. [PubMed: 9765321] Diaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action.
J Neurosci 2005;25:10831–43. [PubMed: 16306396] Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison ofhaloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005;30:1649–61.
[PubMed: 15756305] Eastwood SL, Burnet PW, Harrison PJ. Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia. Biol Psychiatry 2005;57:702–10. [PubMed:15820226] Erdely HA, Tamminga CA, Roberts RC, Vogel MW. Regional alterations in RGS4 protein in schizophrenia. Synapse 2006;59:472–9. [PubMed: 16565965] Farber NB, Heinkel C, Dribben WH, Nemmers B, Jiang X. In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity. Brain Res 2004;1028:66–74. [PubMed: Freedman R. The choice of antipsychotic drugs for schizophrenia. N Engl J Med 2005;353:1286–8.
Fuller R, Nopoulos P, Arndt S, O'leary D, Ho BC, Andreasen NC. Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastictest performance. Am J Psychiatry 2002;159:1183–9. [PubMed: 12091197] Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. Cmaj Gemperle A, Olpe HR. Effects of subchronic clozapine treatment on long-term potentiation in rat prefrontal cortex. Eur Neuropsychopharmacol 2004;14:340–6. [PubMed: 15163446] Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding thecalcineurin gamma subunit. Proc Natl Acad Sci U S A 2003;100:8993–8. [PubMed: 12851458] Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci1999;2:861–3. [PubMed: 10491603] Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001;158:1367–77. [PubMed: 11532718] Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, Mccarley R, Coyle JT.
A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients withschizophrenia. Arch Gen Psychiatry 1999;56:21–7. [PubMed: 9892252] Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM. Dynamic mapping of human corticaldevelopment during childhood through early adulthood. Proc Natl Acad Sci U S A 2004;101:8174–9. [PubMed: 15148381] Gold JM, Goldberg RW, Mcnary SW, Dixon LB, Lehman AF. Cognitive correlates of job tenure among patients with severe mental illness. Am J Psychiatry 2002;159:1395–402. [PubMed: 12153834] Grace AA, Bunney BS, Moore H, Todd CL. Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 1997;20:31–7. [PubMed: 9004417] Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 2000;26:119–36. [PubMed: 10755673] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Green MF, Marder SR, Glynn SM, McGurk SR, Wirshing WC, Wirshing DA, Liberman RP, Mintz J.
The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone. BiolPsychiatry 2002;51:972–8. [PubMed: 12062881] Grunder G, Vernaleken I, Muller MJ, Davids E, Heydari N, Buchholz HG, Bartenstein P, Munk OL, Stoeter P, Wong DF, Gjedde A, Cumming P. Subchronic haloperidol downregulates dopaminesynthesis capacity in the brain of schizophrenic patients in vivo. Neuropsychopharmacology2003;28:787–94. [PubMed: 12655326] Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW. NMDA- dependent modulation of CA1 local circuit inhibition. J Neurosci 1996;16:2034–43. [PubMed:8604048] Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, Gur RC. A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical andneurobehavioral measures. Arch Gen Psychiatry 1998;55:145–52. [PubMed: 9477928] Gurden H, Tassin JP, Jay TM. Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation. Neuroscience1999;94:1019–27. [PubMed: 10625044] Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002;5:405–14. [PubMed:11953750] Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation.
Brain 1999;122(Pt 4):593–624. [PubMed: 10219775] Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:40–68. image 5. [PubMed: 15263907] Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994;151:1409–16. [PubMed: 8092334] Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am JPsychiatry 2000;157:975–81. [PubMed: 10831479] Hippius H. The history of clozapine. Psychopharmacology (Berl) 1989;99(Suppl):S3–5. [PubMed: Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M. Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imagingstudy early in schizophrenia. Arch Gen Psychiatry 2003;60:585–94. [PubMed: 12796222] Hoff AL, Sakuma M, Razi K, Heydebrand G, Csernansky JG, Delisi LE. Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episodeof schizophrenia. Am J Psychiatry 2000;157:1824–8. [PubMed: 11058480] Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA. Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia.
Neuropsychopharmacology 2005;30:2275–82. [PubMed: 16034443] Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA. Sequential regional cerebral blood flow brain scans using PET with H2(15)O demonstrate ketamine actions in CNS dynamically.
Neuropsychopharmacology 2001;25:165–72. [PubMed: 11425500] Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B. Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, MotorBehaviors, and Dopamine Release. Neuropsychopharmacology 2004;29:1259–69. [PubMed:15010696] Hopf FW, Cascini MG, Gordon AS, Diamond I, Bonci A. Cooperative activation of dopamine D1 and D2 receptors increases spike firing of nucleus accumbens neurons via G-protein betagamma subunits.
J Neurosci 2003;23:5079–87. [PubMed: 12832531] Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging.
Brain Res 1979;163:195–205. [PubMed: 427544] Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167–78. [PubMed: 9336221] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Hyman SE, Fenton WS. Medicine. What are the right targets for psychopharmacology? Science Ichikawa J, Chung YC, Li Z, Dai J, Meltzer HY. Cholinergic modulation of basal and amphetamine- induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Brain Res2002;958:176–84. [PubMed: 12468043] Jackson ME, Homayoun H, Moghaddam B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci U S A2004;101:8467–72. [PubMed: 15159546] Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry Jay TM. Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Prog Neurobiol Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration ofphencyclidine. Science 1997;277:953–5. [PubMed: 9252326] Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology1999;20:201–25. [PubMed: 10063482] Jernigan TL, Trauner DA, Hesselink JR, Tallal PA. Maturation of human cerebrum observed in vivo during adolescence. Brain 1991;114(Pt 5):2037–49. [PubMed: 1933232] Ji Y, Pang PT, Feng L, Lu B. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat Neurosci 2005;8:164–72. [PubMed: 15665879] Jodo E, Suzuki Y, Katayama T, Hoshino KY, Takeuchi S, Niwa S, Kayama Y. Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. Cereb Cortex2005;15:663–9. [PubMed: 15342431] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double- blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789–96. [PubMed: 3046553] Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: apharmacological analysis in rats. J Pharmacol Exp Ther 2002;302:1129–34. [PubMed: 12183672] Karlsson P, Smith L, Farde L, Harnryd C, Sedvall G, Wiesel FA. Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients.
Psychopharmacology (Berl) 1995;121:309–16. [PubMed: 8584611] Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM, Rock SL, Woolson S, Tohen M, Tollefson GD, Sanger TM, Lieberman JA. Long-term neurocognitive effects ofolanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry 2006a;59:97–105.
[PubMed: 16140282] Keefe RS, Young CA, Rock SL, Purdon SE, Gold JM, Breier A. One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Schizophr Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER.
Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistentabnormalities in prefrontal cortex functioning. Neuron 2006;49:603–15. [PubMed: 16476668] Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841–5. [PubMed: 10584719] Kita K, Shiratani T, Takenouchi K, Fukuzako H, Takigawa M. Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats. EurNeuropsychopharmacol 1999;9:1–7. [PubMed: 10082221] Koh PO, Bergson C, Undie AS, Goldman-Rakic PS, Lidow MS. Upregulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia. Arch Gen Psychiatry2003;60:311–9. [PubMed: 12622665] Kondziella D, Brenner E, Eyjolfsson EM, Markinhuhta KR, Carlsson ML, Sonnewald U. Glial-Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure.
Neuropsychopharmacology. 2005 Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.
Neuropsychopharmacology 2007;32:1216–23. [PubMed: 17063154] Kraepelin, E. Manic Depressive Insanity and Paranoia. Barclay, RM., translator. Edinburgh, Scotland: Krystal JH, D'souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medicationdevelopment. Psychopharmacology (Berl) 2003;169:215–33. [PubMed: 12955285] Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.
Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry1994;51:199–214. [PubMed: 8122957] La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med 2001;345:224–5. [PubMed: 11463031] Lamberti JS, Olson D, Crilly JF, Olivares T, Williams GC, Tu X, Tang W, Wiener K, Dvorin S, Dietz MB. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry2006;163:1273–6. [PubMed: 16816234] Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 2004;304:839–43. [PubMed: 15073322] Lencz T, Smith CW, Mclaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry 2006;59:863–71.
Leslie CA, Robertson MW, Cutler AJ, Bennett JP Jr. Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis. Brain Res Dev Brain Res1991;62:109–14.
Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002;25:409– Lewis SW, Murray RM. Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia. J Psychiatr Res 1987;21:413–21. [PubMed: 3326936] Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY. N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinicreceptors. Neuropsychopharmacology 2005;30:1986–95. [PubMed: 15900318] Li Z, Ichikawa J, Dai J, Meltzer HY. Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain. Eur J Pharmacol2004;493:75–83. [PubMed: 15189766] Li Z, Ichikawa J, Meltzer HY. A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens.
Psychopharmacology (Berl) 2003;167:315–23. [PubMed: 12664192] Lidow MS, Elsworth JD, Goldman-Rakic PS. Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. J Pharmacol Exp Ther1997;281:597–603. [PubMed: 9103549] Lidow MS, Goldman-Rakic PS. A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex. Proc Natl Acad Sci U S A1994;91:4353–6. [PubMed: 8183912] Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 1999;46:729–39. [PubMed: 10494440] Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, Gilmore J. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. BiolPsychiatry 2001;50:884–97. [PubMed: 11743943] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Lieberman JA, Stroup TS, Mcevoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK. Effectiveness of antipsychotic drugs in patients withchronic schizophrenia. N Engl J Med 2005a;353:1209–23. [PubMed: 16172203] Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, Mcevoy J, Perkins D, Hamer RM, Gu H, Tohen M. Antipsychotic drug effects on brain morphologyin first-episode psychosis. Arch Gen Psychiatry 2005b;62:361–70. [PubMed: 15809403] Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR. BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. EurJ Neurosci 2001;14:135–44. [PubMed: 11488957] Lipska BK, Lerman DN, Khaing ZZ, Weickert CS, Weinberger DR. Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J Neurosci2003;18:391–402. [PubMed: 12887421] Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 2005;46:703–13. [PubMed: 15924857] Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry 1959;81:363–9.
Malenka RC. Synaptic plasticity and AMPA receptor trafficking. Ann N Y Acad Sci 2003;1003:1–11.
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers.
Neuropsychopharmacology 1996;14:301–7. [PubMed: 8703299] Malla A, Payne J. First-episode psychosis: psychopathology, quality of life, and functional outcome.
Schizophr Bull 2005;31:650–71. [PubMed: 16006593] Manoach DS. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 2003;60:285–98. [PubMed: 12591590] Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch GenPsychiatry 2005;62:975–83. [PubMed: 16143729] Mayer S, Harris B, Gibson DA, Blanchard J, Prendergast MA, Holley RC, Littleton J. Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changingthe medium in organotypic hippocampal slice cultures from rat. Alcohol Clin Exp Res 2002;26:655–62. [PubMed: 12045473] Mcevoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK. Effectiveness of clozapine versus olanzapine, quetiapine,and risperidone in patients with chronic schizophrenia who did not respond to prior atypicalantipsychotic treatment. Am J Psychiatry 2006;163:600–10. [PubMed: 16585434] McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, Hawkins KA, Hoffman RE, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A. Randomized,double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.
Am J Psychiatry 2006;163:790–9. [PubMed: 16648318] McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller TJ, Woods SW, Hawkins KA, Hoffman R, Lindborg S, Tohen M, Breier A. The PRIME North America randomized double-blind clinicaltrial of olanzapine versus placebo in patients at risk of being prodromally symptomatic forpsychosis. I. Study rationale and design. Schizophr Res 2003;61:7–18. [PubMed: 12648731] McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, Germano D, Bravin J, Mcdonald T, Blair A, Adlard S, Jackson H. Randomized controlled trial of interventions designed to reducethe risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms.
Arch Gen Psychiatry 2002;59:921–8. [PubMed: 12365879] Melendez RI, Vuthiganon J, Kalivas PW. Regulation of extracellular glutamate in the prefrontal cortex: focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors. JPharmacol Exp Ther 2005;314:139–47. [PubMed: 15769865] Meltzer HY, Burnett S, Bastani B, Ramirez LF. Effects of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry 1990;41:892–7. [PubMed:2401480] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Merrill DB, Ahmari SE, Bradford JM, Lieberman JA. Myocarditis during clozapine treatment. Am J Psychiatry 2006;163:204–8. [PubMed: 16449471] Miles R, Poncer JC, Fricker D, Leinekugel X. The birth (and adolescence) of LTP. J Physiol 2005;568:1– Milev P, Ho BC, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up.
Am J Psychiatry 2005;162:495–506. [PubMed: 15741466] Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD,Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors inschizophrenia that regulate cAMP signaling. Science 2005;310:1187–91. [PubMed: 16293762] 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;55:1013–22.
[PubMed: 15121486] Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S.
Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related toschizophrenia. Proc Natl Acad Sci U S A 2003;100:8987–92. [PubMed: 12851457] Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron 2003;40:881–4.
Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997;17:2921–7. [PubMed: 9092613] Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998;281:1349–52. [PubMed: 9721099] Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994;12:529–40.
[PubMed: 7512349] Moore H, Todd CL, Grace AA. Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons. J Neurosci 1998;18:5068–77. [PubMed:9634572] Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission andvulnerability to cocaine seeking. J Neurosci 2005;25:6389–93. [PubMed: 16000629] Murray AM, Waddington JL. The interaction of clozapine with dopamine D1 versus dopamine D2 receptor-mediated function: behavioural indices. Eur J Pharmacol 1990;186:79–86. [PubMed:2149339] Naassila M, Hammoumi S, Legrand E, Durbin P, Daoust M. Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcohol Clin ExpRes 1998;22:802–9. [PubMed: 9660304] O'donnell P, Lewis BL, Weinberger DR, Lipska BK. Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cereb Cortex2002;12:975–82. [PubMed: 12183396] Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC. Structural maturation of neural pathways in children and adolescents: in vivo study. Science 1999;283:1908–11. [PubMed: 10082463] Paz RD, Andreasen NC, Daoud SZ, Conley R, Roberts R, Bustillo J, Perrone-Bizzozero NI. Increased expression of activity-dependent genes in cerebellar glutamatergic neurons of patients withschizophrenia. Am J Psychiatry 2006;163:1829–31. [PubMed: 17012697] Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry2005;162:1785–804. [PubMed: 16199825] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Pierrefiche O, Daoust M, Naassila M. Biphasic effect of acamprosate on NMDA but not on GABAA receptors in spontaneous rhythmic activity from the isolated neonatal rat respiratory network.
Neuropharmacology 2004;47:35–45. [PubMed: 15165832] Pillai A, Parikh V, Terry AV Jr, Mahadik SP. Long-term antipsychotic treatments and crossover studies in rats: Differential effects of typical and atypical agents on the expression of antioxidant enzymesand membrane lipid peroxidation in rat brain. J Psychiatr Res. 2006a Pillai A, Terry AV Jr, Mahadik SP. Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res 2006b;82:95–106. [PubMed: 16442781] Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, Wu JC, Alva G, Carreon DT, Bunney WE Jr, Fallon JH, Kennedy JL. D1 receptor alleles predict PET metabolic correlates of clinical responseto clozapine. Mol Psychiatry 2003;8:109–13. [PubMed: 12556915] Prasad KM, Chowdari KV, Nimgaonkar VL, Talkowski ME, Lewis DA, Keshavan MS. Genetic polymorphisms of the RGS4 and dorsolateral prefrontal cortex morphometry among first episodeschizophrenia patients. Mol Psychiatry 2005;10:213–9. [PubMed: 15381923] Rabinowitz J, De Smedt G, Harvey PD, Davidson M. Relationship between premorbid functioning and symptom severity as assessed at first episode of psychosis. Am J Psychiatry 2002;159:2021–6.
[PubMed: 12450951] Reichenberg A, Weiser M, Rapp MA, Rabinowitz J, Caspi A, Schmeidler J, Knobler HY, Lubin G, Nahon D, Harvey PD, Davidson M. Elaboration on premorbid intellectual performance in schizophrenia:premorbid intellectual decline and risk for schizophrenia. Arch Gen Psychiatry 2005;62:1297–304.
Room R, Babor T, Rehm J. Alcohol and public health. Lancet 2005;365:519–30. [PubMed: 15705462] Rosenheck R, Leslie D, Keefe R, Mcevoy J, Swartz M, Perkins D, Stroup S, Hsiao JK, Lieberman J.
Barriers to employment for people with schizophrenia. Am J Psychiatry 2006;163:411–7. [PubMed:16513861] Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG. In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycleand functional neuroenergetics. Philos Trans R Soc Lond B Biol Sci 1999;354:1165–77. [PubMed:10466144] Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans:a 4-T proton MRS study. Am J Psychiatry 2005;162:394–6. [PubMed: 15677610] Rund BR, Melle I, Friis S, Larsen TK, Midboe LJ, Opjordsmoen S, Simonsen E, Vaglum P, McGlashan T. Neurocognitive dysfunction in first-episode psychosis: correlates with symptoms, premorbidadjustment, and duration of untreated psychosis. Am J Psychiatry 2004;161:466–72. [PubMed:14992972] Rycroft BK, Gibb AJ. Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors. Neuropharmacology 2004;47:505–14. [PubMed: 15380369] Saugstad JA, Marino MJ, Folk JA, Hepler JR, Conn PJ. RGS4 inhibits signaling by group I metabotropic glutamate receptors. J Neurosci 1998;18:905–13. [PubMed: 9437012] Sawaguchi T, Goldman-Rakic PS. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotordelayed-response task. J Neurophysiol 1994;71:515–28. [PubMed: 7909839] Schonfeldt-Lecuona C, Connemann BJ. Sweet's syndrome and polyserositis with clozapine. Am J Psychiatry 2002;159:1947. [PubMed: 12411238] Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 1975;188:1217–9. [PubMed: 1145194] Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, Tossell JW, Lenane M, Rapoport JL. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison.
Arch Gen Psychiatry 2006;63:721–30. [PubMed: 16818861] Sher L. Alcoholism and suicidal behavior: a clinical overview. Acta Psychiatr Scand 2006a;113:13–22.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Sher L. Dopamine and the pathophysiology of suicidal behavior in alcoholism. Med Hypotheses 2006b; Smith KE, Gibson ES, Dell'acqua ML. cAMP-dependent protein kinase postsynaptic localization regulated by NMDA receptor activation through translocation of an A-kinase anchoring proteinscaffold protein. J Neurosci 2006;26:2391–402. [PubMed: 16510716] Smith WB, Starck SR, Roberts RW, Schuman EM. Dopaminergic stimulation of local protein synthesis enhances surface expression of GluR1 and synaptic transmission in hippocampal neurons. Neuron2005;45:765–79. [PubMed: 15748851] So CH, Varghese G, Curley KJ, Kong MM, Alijaniaram M, Ji X, Nguyen T, O'dowd B F, George SR.
D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation ofeither receptor. Mol Pharmacol 2005;68:568–78. [PubMed: 15923381] Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci 2003;6:309–15. [PubMed: 12548289] Sowell ER, Thompson PM, Holmes CJ, Batth R, Jernigan TL, Toga AW. Localizing age-related changes in brain structure between childhood and adolescence using statistical parametric mapping.
Neuroimage 1999;9:587–97. [PubMed: 10334902] Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U. The clockgene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med2005;11:35–42. [PubMed: 15608650] Sun X, Zhao Y, Wolf ME. Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. J Neurosci 2005;25:7342–51. [PubMed: 16093384] Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, Mckinzie DL, Fienberg AA, Nomikos GG, Greengard P. Diverse psychotomimetics act through a common signaling pathway.
Science 2003;302:1412–5. [PubMed: 14631045] Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005;4:131–44.
[PubMed: 15665858] Tarazi FI, Tomasini EC, Baldessarini RJ. Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study. Dev Neurosci 1999;21:43–9.
[PubMed: 10077701] Tauscher J, Hussain T, Agid O, Verhoeff NP, Wilson AA, Houle S, Remington G, Zipursky RB, Kapur S. Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation fromother atypical antipsychotics. Am J Psychiatry 2004;161:1620–5. [PubMed: 15337652] Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, Neufeld RW, Rogers J, Pavlosky W, Schaefer B, Densmore M, Alsemaan Y, Williamson PC. Glutamate and glutamine measured with4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am JPsychiatry 2002;159:1944–6. [PubMed: 12411236] Tibbo P, Hanstock C, Valiakalayil A, Allen P. 3-T proton MRS investigation of glutamate and glutamine in adolescents at high genetic risk for schizophrenia. Am J Psychiatry 2004;161:1116–8. [PubMed:15169703] Toga AW, Thompson PM, Sowell ER. Mapping brain maturation. Trends Neurosci 2006;29:148–59.
Tseng KY, Amin F, Lewis BL, O'donnell P. Altered prefrontal cortical metabolic response to mesocortical activation in adult animals with a neonatal ventral hippocampal lesion. Biol Psychiatry 2006a;60:585–90. [PubMed: 16780812] Tseng KY, Lewis BL, Lipska BK, O'donnell P. Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia. BiolPsychiatry 2007;62:730–8. [PubMed: 17207473] Tseng KY, Mallet N, Toreson KL, Le moine C, Gonon F, O'donnell P. Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo. Synapse 2006b;59:412–7. [PubMed: 16485264] Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.
Tseng KY, O'donnell P. Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 2004;24:5131–9. [PubMed:15175382] Tseng KY, O'donnell P. Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation. Cereb Cortex 2005;15:49–57. [PubMed: 15217899] Tseng KY, O'donnell P. D2 dopamine receptors recruit a GABA component for their attenuation of excitatory synaptic transmission in the adult rat prefrontal cortex. Synapse 2007a;61:843–50.
[PubMed: 17603809] Tseng KY, O'donnell P. Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex 2007b;17:1235–40. [PubMed: 16818475] Tyler WJ, Pozzo-Miller LD. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci2001;21:4249–58. [PubMed: 11404410] Van Oel CJ, Sitskoorn MM, Cremer MP, Kahn RS. School performance as a premorbid marker for schizophrenia: a twin study. Schizophr Bull 2002;28:401–14. [PubMed: 12645673] Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, Mcevoy JP, Lieberman JA.
Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine,olanzapine, risperidone, or haloperidol. J Clin Psychiatry 2004;65:57–61. [PubMed: 14744169] Waszczak BL, Martin LP, Finlay HE, Zahr N, Stellar JR. Effects of individual and concurrent stimulation of striatal D1 and D2 dopamine receptors on electrophysiological and behavioral output from ratbasal ganglia. J Pharmacol Exp Ther 2002;300:850–61. [PubMed: 11861790] Webster MJ, Weickert CS, Herman MM, Kleinman JE. BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Brain Res Dev Brain Res2002;139:139–50.
Wehmeier PM, Heiser P, Remschmidt H. Pancreatitis followed by pericardial effusion in an adolescent treated with clozapine. J Clin Psychopharmacol 2003;23:102–3. [PubMed: 12544384] Weickert CS, Ligons DL, Romanczyk T, Ungaro G, Hyde TM, Herman MM, Weinberger DR, Kleinman JE. Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients withschizophrenia. Mol Psychiatry 2005;10:637–50. [PubMed: 15940304] Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660–9. [PubMed: 3606332] Weiser M, Reichenberg A, Rabinowitz J, Kaplan Z, Mark M, Bodner E, Nahon D, Davidson M.
Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onsetof schizophrenia. Arch Gen Psychiatry 2001;58:959–64. [PubMed: 11576035] Wiersma D, Wanderling J, Dragomirecka E, Ganev K, Harrison G, An Der Heiden W, Nienhuis FJ, Walsh D. Social disability in schizophrenia: its development and prediction over 15 years inincidence cohorts in six European centres. Psychol Med 2000;30:1155–67. [PubMed: 12027051] Williams K, Russell SL, Shen YM, Molinoff PB. Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron 1993;10:267–78. [PubMed: 8439412] Williams SH. Medications for treating alcohol dependence. Am Fam Physician 2005;72:1775–80.
Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull 1991;17:325–51.
Zahrt J, Taylor JR, Mathew RG, Arnsten AF. Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 1997;17:8528–35. [PubMed: 9334425] Zecevic N, Bourgeois JP, Rakic P. Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life. Brain Res Dev Brain Res 1989;50:11–32.
Zecevic N, Rakic P. Synaptogenesis in monkey somatosensory cortex. Cereb Cortex 1991;1:510–23.
Eur Neuropsychopharmacol. Author manuscript; available in PMC 2010 March 3.

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