Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists John H. Krystal, M.D., Aysenil Belger, Ph.D., D. Cyril D’Souza, Amit Anand, M.D., Dennis S. Charney, M.D., George K. Aghajanian, M.D., and Bita Moghaddam, Ph.D.

Antagonists of the N-methyl-D-aspartate (NMDA) Recent preclinical and clinical studies also suggest that subtype of glutamate produce transient effects in that attenuate glutamate release, including group healthy human subjects that resemble symptoms observed II/III metabotropic glutamate-receptor , drugs that in some schizophrenic patients. NMDA antagonists also block voltage-dependent ion channels, and serotonin-2A impair aspects of human corticolimbic information (5-HT2A)-receptor antagonists may attenuate NMDA processing in a fashion that resembles deficits associated antagonist effects. To the extent that NMDA antagonist with schizophrenia, as measured by electrophysiologic and effects provide insight into the pathophysiology of functional neuroimaging paradigms. Although all current schizophrenia, these novel pharmacologic strategies and block -2 (D2) receptors, recent others may provide a rationale for the exploration of new studies question the centrality of D2-receptor stimulation to treatments that do not involve D2-receptor blockade. If the NMDA-antagonist psychosis. For example, pretreatment schizophrenia, like NMDA-antagonist effects, involves with fails to attenuate the psychotic effects of hyperglutamatergic states, then these novel in healthy human subjects. Also, pretreatment pharmacotherapeutic strategies also may have with fails to increase these effects of ketamine. neuroprotective or neurotrophic consequences that influence Both preclinical and clinical studies suggest that the course of schizophrenia. [Neuropsychopharmacology subanesthetic doses of NMDA antagonists activate 22:S143–S157, 1999] © 1999 American College of glutamate neurons in the cerebral cortex and hippocampus. Neuropsychopharmacology. Published by Elseiver Science Inc.

KEY WORDS: Glutamate; NMDA; Ketamine; Schizophrenia; The field of schizophrenia research is rapidly moving Frontal cortex; Attention; Cognitive function; from a focus on the contributions of single neurotrans- Pharmacotherapy; ; Serotonin; 5-HT2A; mitters or brain regions toward an appreciation of the LY354740; M100907; MDL 100,907 interactions of multiple neurotransmitter systems, neural networks, and intracellular mechanisms (Aghajanian and Marek 1999; Carlsson et al. 1997; Krystal et al. From the Department of Psychiatry (JHK, AB, DCD, AA, DSC, GKA, BM), Yale University School of Medicine, New Haven, Con- 1999b). Investigators are abandoning oversimplified necticut; Psychiatry Service (JHK, AB, DCD, AA, DSC, GKA, BM), models suggesting that all activation is VA Connecticut Healthcare System, West Haven, Connecticut; detrimental to symptoms in schizophrenic patients. In- Abraham Ribicoff Research Facilities (JHK, DSC, GKA, BM), Con- necticut Mental Health Center, New Haven, Connecticut, USA. stead, optimal levels of stimulation of particular dopa- Address correspondence to: John H. Krystal, M.D., Psychiatry mine-receptor subtypes are needed to sustain behavior Service (116-A), VA Connecticut Healthcare System, 950 Campbell and higher cognitive functions (Arnsten 1997; Gold- Avenue, West Haven, CT 06516. Tel.: 203-937-4790. Fax: 203-937- 3468. E-mail: [email protected] man-Rakic and Selemon 1997). Concurrently, psychiat- Received June 24, 1999; accepted August 2, 1999. ric researchers are assimilating both the promise and

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. S6 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00102-5

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shortcomings of both typical and atypical neuroleptics 1992; Reich and Silvay 1989; White et al. 1982). Building (Meltzer 1997). As a result, it is now timely to consider on this foundation, a series of rigorous psychopharma- the possibility that the next era in develop- cological studies, using validated measures for assess- ment for treating schizophrenia will involve mecha- ing the signs and symptoms of schizophrenia, were ini- nisms other than dopamine-2 (D2)-receptor antagonism. tiated that documented the cognitive and behavioral This review highlights a novel perspective on the effects of ketamine in healthy human subjects (Krystal neurobiology and treatment of schizophrenia growing et al. 1994a; Malhotra et al. 1996; Newcomer et al. 1999). from the study of the effects of the N-methyl-D-aspar- As noted in Table 1, the new generation of studies tate (NMDA) glutamate-receptor antagonists in ani- suggested that subanesthetic ketamine doses produced mals and humans. It considers parallels between the three clusters of symptoms in healthy subjects that have transient symptomatic effects of single doses of NMDA been described in schizophrenic patients: positive, neg- antagonists in healthy human subjects and findings in ative, and disorganization symptoms (Andreasen et al. schizophrenic patients. It then highlights similarities 1995; Liddle and Morris 1991). The extent to which ket- between disturbances in information processing pro- amine produces these effects is related to the dose and duced by NMDA antagonists and deficits observed in rate of infusion (Krystal et al. 1994a; Newcomer et al. schizophrenic patients. Next, this review attempts to 1999). The positive symptoms produced by ketamine provide some insights into mechanisms that link included grandiose and paranoid delusions, bizarre NMDA-receptor antagonism to activa- ideation, profound perceptual alterations, and, less fre- tion and information-processing deficits. This review quently, hallucinations. In some subjects, the positive then summarizes evidence that dopaminergic systems symptoms produced by ketamine are indistinguishable have limited contributions to positive and negative from symptoms seen in schizophrenic patients (Krystal symptoms produced by NMDA antagonists. Finally, it et al. 1999a). However, the positive symptoms pro- considers the utility of facilitation of the -B site duced by ketamine also show differences from symptoms of the NMDA-receptor complex and drugs that attenuate seen in schizophrenia. For example, auditory hallucina- glutamate release as pharmacotherapies for schizophre- nia based on their capacity to attenuate the effects of NMDA antagonists in animals and humans. Because glutamate has both neurotrophic and neurotoxic effects in the brain, potential implications of glutamatergic Table 1. Similarity and Dissimilarity of Ketamine Effects in Healthy Human Subjects to Signs and Symptoms of pharmacotherapies for the course of schizophrenia is Schizophrenia considered. Positive symptoms • Delusions • Perceptual alterations/ hallucinations PARALLELS BETWEEN NMDA-ANTAGONIST Negative symptoms • Blunted affect • Emotional withdrawal EFFECTS IN HEALTHY SUBJECTS AND Disorganization symptons • Loose associations SCHIZOPHRENIC PATIENTS • Tangentiality • Thought blocking Luby and his colleagues coined the term “schizo- • Perseveration phrenomimetic” to describe the striking similarities be- • Disorganized behavior Cognitive deficits associated • Distractibility tween the effects of (PCP), and the symp- with frontal cortical ciruits • Reduced verbal fluency toms of schizophrenia (Luby et al. 1959). The identification • Concreteness of thought of NMDA-receptor antagonism as the mechanism of ac- • Impairments in planning tion of PCP, the implication of NMDA receptors in • Working memory deficits many fundamental aspects of neural plasticity and neu- • Impairment of smooth pursuit eye-tracking rotoxicity, and reports of altered glutamate-receptor • Reduced cortical activation binding in postmortem tissue from schizophrenic pa- while performing the tients rekindled interest in the effects of PCP (Anis et al. oddball task 1983; Krystal et al. 1999b; Madison et al. 1991; Rothman Cognitive deficits associated • Disruption of new learning and Olney 1987; Zukin and Zukin 1979). Although ethi- with temporohippocampal • Reduced prepulse inhibition circuits of the startle response cal considerations prohibited the exploration of PCP ef- Mood effects • Euphoria fects in humans, its derivative, ketamine, was a widely • Anxiolysis (low-dose) used anesthetic agent approved by the United States • (high-dose) Food and Administration with an established and Other perceptual effects • Distortion in body extensive record of safety in healthy humans (Domino perception • Distortion of time perception et al. 1965; Green and Johnson 1990; Haas and Harper

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tions are produced infrequently by ketamine. Also, per- 1994b). Ketamine preferentially interferes with learning ceptual alterations that more closely resemble dissocia- the abstract matching rules on the WCST and relatively tive states are a prominent behavioral effect of ketamine spares performance on this test once matching rules are (Krystal et al. 1995). Clinical experience with NMDA learned (Krystal et al. 1999c). This finding challenges antagonists in environments with varying levels of vi- the view that subanesthetic doses of ketamine produce sual and auditory stimulation suggests that the degree diffuse cognitive impairment or delerium. Ketamine to which NMDA antagonists produce symptoms within also produces encoding deficits in tests of working a given sensory domain (e.g., visual, auditory) is related memory and short-term memory (Ghoneim et al. 1985; to the extent of environmental stimulation within that Krystal et al. 1994a; Malhotra et al. 1996; Newcomer et al. sensory domain (Krystal et al. 1999a; Krystal et al. 1999; Øye et al. 1992). 1998a). Thus, dose, pharmacokinetic issues, and envi- Recent interest in chronic or intermittent (binge ronmental manipulations may influence the degree to related) NMDA-antagonist effects as models for the which ketamine effects seem similar to the positive pathophysiology of schizophrenia has not been paral- symptoms of schizophrenia. leled by informative clinical trials (Jentsch and Roth The interpretation of negative symptoms produced 1999). Interest in chronic NMDA-antagonist adminis- by ketamine in healthy individuals is also complicated. tration stems, in part, from the suspicion that protracted Ketamine-induced negative symptoms include blunted psychoses observed in association with the abuse of affect, emotional withdrawal, and psychomotor retar- NMDA antagonists in nonpsychotic populations reflect dation. Negative symptoms produced by ketamine may a characteristic of chronic or repeated intermittent ad- be confounded by the sedative effects of this drug. For ministration of NMDA antagonists (Allen and Young example, premedication with two sedating medica- 1978; Fauman et al. 1976). However, these naturalistic tions, lorazepam 2 mg or 25 mg, increased studies are quite problematic to interpret for a number negative symptoms produced by ketamine in healthy of reasons: (1) it is not clear whether chronic psychosis human subjects (Krystal et al. 1998b; Lipschitz et al. in this population reflects a preexisting predisposition 1997). However, at similarly sedating doses, ketamine for psychosis; (2) NMDA antagonists, when abused, are clearly produced more negative symptoms than both frequently intermixed with other propsychotic sub- lorazepam and haloperidol (Krystal et al. 1999d; Krystal stances, resulting in a confusing admixture of effects; et al. 1998b). Also, negative symptoms in schizophrenic (3) individuals may be misled regarding the actual com- patients have been divided into primary symptoms in- position of street drugs called PCP or ketamine; and (4) trinsic to the disorder, and secondary symptoms arising there may be a bias to attribute psychoses emerging in as a consequence of state-related changes or factors ex- people with a history of PCP use to ingestion of that trinsic to the pathophysiology of schizophrenia, such as drug. To date, there are no laboratory-based psycho- (Carpenter et al. 1988). Ket- pharmacologic studies of healthy populations adminis- amine produces bradykinesia in healthy human sub- tered ketamine or PCP on a chronic basis. Ketamine jects, and this action may contribute to the induction of does not seem to produce a schizophrenia-like syn- secondary negative symptoms (Krystal et al. 1999d). drome when administered chronically to treat chronic In healthy subjects, ketamine produces cognitive im- pain (Krystal et al. 1999e). However, these studies were pairment and behavioral disorganization in healthy not designed to evaluate the impact of ketamine binges. subjects that resemble those seen in some schizophrenic Furthermore, chronic administration of the NMDA an- patients. Two studies found that subanesthetic ket- tagonist, amantidine, seems to be relatively well-toler- amine produced thought disorder in healthy subjects as ated by most schizophrenic patients (Di Mascio et al. measured by Gorham’s proverb test (Krystal et al. 1976; Flaherty and Bellur 1981; Konig et al. 1996). Thus, 1999d; Krystal et al. 1998b). After ketamine administra- it is premature to conclude that chronic NMDA-antago- tion, thought processes become concrete and overper- nist administration is superior to acute NMDA-antago- sonalized. Loose associations, tangentiality, persevera- nist administration in modeling the signs and symp- tion, and thought blocking are also common. Recently, toms of schizophrenia. ketamine-induced thought disorder in healthy subjects In summary, there are many clinical parallels be- proved to be essentially indistinguishable from thought tween the acute effects of ketamine or PCP and the phe- disorder in a group of schizophrenic patients (Adler et nomenology of schizophrenia. However, ketamine effects al. 1998). in healthy human subjects are not identical to schizo- Other cognitive impairments produced by ketamine phrenia. It is not yet clear whether the differences be- also resemble those associated with schizophrenia. Ket- tween NMDA antagonist effects and schizophrenia re- amine impairs performance on several cognitive tests flect a substantial impediment for using NMDA associated with the frontal cortex including verbal flu- antagonist effects to gain insights into the pathophysi- ency and the Wisconsin Card Sorting Test (WCST) ology or treatment of schizophrenia. However, caution (Krystal et al. 1999d; Krystal et al. 1998b; Krystal et al. is clearly justified in this regard. As has been suggested

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previously (Abi-Saab et al. 1998), a cautious first step reduced dorsolateral prefrontal cortex (middle frontal may be to determine those elements of acute or chronic gyrus) and anterior cingulate cortex activity, but pre- ketamine response that are relevant to schizophrenia. served parieto-occipital cortex activation while perform- ing a visual oddball task, as assessed using functional magnetic resonance imaging (fMRI) (Belger et al. 1997). Similarities in Information-Processing Deficits Recent studies suggest that in healthy subjects ket- Associated with Schizophrenia and Ketamine amine produces a similar pattern of information pro- Administration in Healthy Human Subjects cessing deficits that is similar to the pattern in schizo- The neurobiological substrates for cognitive deficits in phrenic patients. It impairs the ability to both effectively schizophrenia are of great interest at a time when devel- gate the processing of sensory stimuli and process sa- oping novel treatments targeting these deficits has lient stimuli. For example, ketamine increases distracti- emerged as a priority. Schizophrenic patients are im- bility (Krystal et al. 1999d; Krystal et al. 1998b) and it paired in their capacity to attend to important or salient may depress startle PPI (Krystal et al. 1999f) in healthy information and to ignore irrelevant or distracting in- humans. Furthermore, ketamine reduces the activation formation in the environment. Behavioral studies show of the dorsolateral prefrontal cortex and anterior cingu- that attention deficits precede the onset of schizophrenia late cortex, but not parietal cortex, during the perfor- and predict the development of symptoms in individu- mance of the oddball task, as assessed with event-related als at high risk for developing this disorder (Freedman fMRI (Krystal et al. 1998b). Reductions in cortical acti- et al. 1998). vation during the oddball task are consistent with ket- Electrophysiologic studies have helped to establish amine-induced reductions in P300 amplitude in healthy the view that attention dysfunction in schizophrenia re- subjects (Umbricht et al. 1999). In this study, ketamine flects disturbances at several levels within corticolimbic effects on N200 and N100 were less prominent than its networks (Boutros et al. 1999). Two techniques, in par- effects on P300. This differential effect is consistent with ticular, have been used to suggest that patients have im- the fMRI study in suggesting that subanesthetic ket- pairments in inhibiting their response to sensory input. amine preferentially interferes with the frontal “execu- For example, when presented with pairs of clicks, tive” control of information processing relative to its ef- schizophrenic patients do not show a normal suppres- fects on regions engaged at earlier stages of information sion of the midlatency evoked response (P50), an action processing. that may involve the hippocampus (Freedman et al. As noted earlier, the drive to develop effective phar- 1996). Similarly, schizophrenic patients show a reduced macotherapies for information-processing deficits in capacity to inhibit their startle response to a loud noise schizophrenic patients places a premium on the ratio- (pulse) that is preceeded by a brief quiet noise (prepulse) nal development of pharmacotherapies targeting these (Braff et al. 1978). Prepulse inhibition (PPI) of the startle deficits. This approach will likely depend on the gener- response has an increasingly well-defined corticolimbic ation of accurate pathophysiological hypotheses. In the circuitry (Swerdlow and Geyer 1998). PPI deficits in next sections, mechanisms that may underlie the simi- schizophrenic patients seem to be related to inefficiency larities between information-processing deficits pro- in response selection related to the failure to ignore dis- duced by ketamine and those observed in schizo- tracting environmental information (Karper et al. 1996). phrenic patients are considered. Convergent electrophysiologic and functional neu- roimaging findings provide support for the view that frontal cortical activation deficits in schizophrenic pa- Hyperglutamatergic Consequences of tients are related to disruption of the processing of im- Subanesthetic NMDA-Receptor Antagonism, portant environmental information. For example, novelty Circuit Dysfunction, and Schizophrenia is a key element related to the salience of environmental stimuli. Normally, when stimuli are presented repeat- The ability of NMDA antagonists to block an excitatory edly, the subject habituates to their presentation and ig- glutamate-receptor subclass suggested that these drugs nores their presence. However, when a novel stimulus represented a model for functional deficits in cortical appears among the background stimuli, that is, an glutamate systems (Carlsson and Carlsson 1990; Javitt “oddball,” the subject focuses attention on the novel and Zukin 1991). Furthermore, several preclinical para- stimulus. In this “oddball paradigm,” presentations of digms have clearly demonstrated that NMDA-receptor novel stimuli elicit a characteristic electrophysiologic antagonists block a component of glutamatergic neu- signal, the P300. Schizophrenic patients show reduc- ronal excitation and neurotoxicity mediated by stimula- tions in the amplitude and latency of the P300 response tion of this subclass (Anis et al. 1983; that are related to attention deficits (Grillon et al. 1990) Krystal et al. 1999e; Rothman and Olney 1987). and the presence of particular symptoms (Belger, un- Consistent with the cognitive effects of NMDA an- published data). Similarly, schizophrenic patients show tagonists, the excitatory actions of NMDA receptors

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have an associative function stemming from the fact AMPA or kainate receptors (Schiller et al. 1998; Segal that they are both ligand-gated and voltage dependent 1995; Yuste et al. 1999). When the postsynaptic neuron (Figure 1) (Schiller et al. 1998; Yuste et al. 1999). Under is stimulated—simulating the convergent excitatory in- basal conditions, ions act as a noncompeti- put—the magnesium blockade is displaced, and the tive antagonist of this receptor; that is, a plug for the same degree of glutamatergic stimulation produces a calcium channel. When the postsynaptic neuron is acti- greatly enhanced calcium entry via the additional con- vated (partially depolarized), the magnesium plug is tribution of NMDA receptors. displaced, and the combined binding of glutamate and However, there is growing evidence that subanes- glycine evokes the entry of calcium via the NMDA re- thetic doses of NMDA-receptor antagonists produce ceptor-coupled channel. This process is associative, be- hyperactivity of glutamatergic pyramidal neurons in cause glutamate release by the presynaptic neuron, via cortical and limbic regions that results in stimulation of NMDA receptors, can serve to amplify the signal gener- non-NMDA glutamate receptors (Moghaddam et al. ated by another neuronal input; that is, the one that 1997; Patel and McCulloch 1995). For example, NMDA produced the initial partial depolarization of the post- antagonists preferentially attenuate the activity of in- synaptic neuron. This interaction is nicely illustrated at hibitory interneurons in the hippocampus that mediate the level of the dendritic spine in layer V cortical pyrami- feedforward and feedback inhibition, resulting in in- dal neurons (Schiller et al. 1998) or hippocampal CA1 creased spiking by pyramidal neurons (Grunze et al. pyramidal neurons (Yuste et al. 1999). Dendritic spines 1996). Furthermore, this study showed that NMDA an- are key structures for integrating neuronal input, and tagonists more potently block the long-term potentia- NMDA receptors are preferentially localized to these tion (LTP) of inhibitory neurons than of pyramidal neu- spines (Conti 1997). In the brain slice, presynaptic acti- rons. Similarly, as presented in Figure 2, subanesthetic vation produces a moderate level of calcium entry via doses of NMDA antagonists stimulate glutamate re- voltage-dependent calcium channels, thought to be of lease in the prefrontal cortex when administered sys- the L-, N-, and P-subtypes as well as calcium-permeable temically (Moghaddam et al. 1997; Moghaddam and

Figure 1. This figure illustrates the modulatory associative function of NMDA receptors in dendritic spines. Dendritic spines are key structures that permit neurons to integrate inputs. Excitatory input to the presynaptic and postsynaptic neurons via non-NMDA mechanisms is not associative. Therefore, release of glutamate from the presynaptic neuron or stimulation of the postsynaptic neuron produces calcium influx through a variety of mechanisms, including voltage-sensitive calcium chan- nels (VSCC) and calcium-fluxing AMPA and kainate receptors. It is only when both the presynaptic neuron and postsynap- tic neuron are simultaneously activated that the magnesium block is displaced from the NMDA-receptor channel, and glutamate release recruits NMDA receptors. Thus, NMDA-receptor stimulation serves to enhance synaptic function at syn- apses where there is convergent activating input. This type of convergent activation is essential for many forms of neural plasticity involving NMDA receptors, including long-term potentiation (from Schiller et al. 1998; Yuste et al. 1999).

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Adams 1998). As with the hippocampus, reductions in Cerebral metabolic studies in both rodents and humans GABAergic interneuron activity may contribute to en- support the view that subanesthetic doses of NMDA hanced glutamate release in this region (Olney and Farber antagonists produce regional cortical metabolic activa- 1995b). This view is supported by preliminary data sug- tion. For example, several studies suggest that cortical gesting that local injection of NMDA antagonists into glucose metabolism is increased regionally in animals the prefrontal cortex enhance glutamate release in this administered NMDA antagonists (Clow et al. 1991; Ku- region (Moghaddam, personal communication). rumaji and McCulloch 1990; Nehls et al. 1988; Tam- However, other mechanisms may also contribute to minga et al. 1987). Similarly, ketamine increases frontal the hyperglutamatergic effects of NMDA antagonists. cortex cerebral blood flow and glucose metabolism in For example, disinhibition of glutamate neurons would healthy human subjects (Breier et al. 1997) and schizo- be predicted to produce feedforward activation via lo- phrenic patients (Lahti et al. 1995a). Linking glutamate cal projections (Lubke et al. 1996) and through projec- to these metabolic findings, changes in cortical glucose tions to other brain regions that send excitatory projec- metabolism are closely associated with parallel changes tions to the cortex, including the thalamus and amygala in cortical glutamatergic neurotransmission (Magistretti (Groenewegen et al. 1997). Furthermore, systemic ad- and Pellerin 1997; Sibson et al. 1997; Sibson et al. 1998). ministration of NMDA antagonists facilitates raphe Neural network modeling studies may be helpful in neuronal activity and serotonin release in the cortex resolving the seeming paradox that NMDA-receptor (Jentsch et al. 1997; Lejeune et al. 1994; Lindefors et al. antagonists activate prefrontal cortex metabolism and

1997). In turn, serotonin-2A (5-HT2A)-receptor stimula- yet impair information-processing functions associated tion activates prefrontal cortical pyramidal neurons in with the prefrontal cortex and hippocampus. A simpli- layer V via 5-HT2A receptors located on their apical den- fied introduction to this hypothesis is presented below. drites (Aghajanian and Marek 1997; Jakab and Gold- It is assumed that functional output from cortical net- man-Rakic 1998). works is generated when pyramidal neurons reach a

Figure 2. This simplified schematic illustrates mechanisms through which NMDA antagonists might produce loss of functional selectivity and glutamatergic hyperactivity within a cortical or hippocampal network. The left figure illustrates the normal function of this imaginary circuit. Excitatory glutamatergic cortico–cortico or thalamo–cortical inputs (terminals with “ϩ” sign) make contact with pyramidal neurons (triangle) or GABA interneuron (octagon). These synapses involve NMDA and other excitatory receptors as illustrated in Figure 1. In addition, there is feedforward inhibition of pyramidal neurons medi- ated by glutamatergic excitation of interneurons. As a result, when there is selectivity in the strength of inputs to particular neurons (represented as a stronger input to the middle neuron), the result is a selective and proportionate glutamatergic activation (represented as the selective activation of the middle pyramidal neuron). The right figure illustrates the impact of NMDA antagonists. This figure highlights changes from the left figure and therefore redundant information is omitted to achieve clarity. Low doses of NMDA antagonists attenuate the activation of interneurons resulting in disinhibition of all three pyramidal neurons. As a result, the functional specificity of the inputs of graded intensity is lost as all neurons are acti- vated. Thus, NMDA antagonists produce glutamatergic hyperactivity that may be dysfunctional (modified from Lisman et al 1998; see also Grunze et al. 1996; Aghajanian and Marek 1999, Williams and Goldman-Rakic, personal communication).

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threshold of activation that produces an information- (Grossberg 1984; Lisman et al. 1998) predict that hypo- bearing signal. Similarly, it is critical to avoid the activa- glutamatergic states (reduced glutamatergic signal or tion of extraneous neurons and to terminate the activa- excessive inhibition) and hyperglutamatergic states (in- tion of task-related neurons appropriately in order to hibitory deficits or heightened activation) could seem to minimize interference or “noise.” produce similar disruptions in information processing. NMDA-receptor antagonists seem to disrupt the ca- Thus, the fact that ketamine and schizophrenia are asso- pacity of cortical networks to process information effi- ciated with similar physiological and behavioral output ciently, because they interfere with the spatial (i.e., the abnormalities (i.e., signs and symptoms) does not nec- number of activated neurons) and temporal selectivity essarily imply that schizophrenia is also a hyper- of task-related cortical pyramidal activation (Figure 2) glutamatergic state. (Grunze et al. 1996; Lisman et al. 1998). As noted earlier, In fact, the literature describing cortical metabolic the associative functions of the NMDA receptor seem to changes in schizophrenia contains conflicting findings. depend on the convergence of glutamatergic neuronal The finding of metabolic hypofrontality in schizo- inputs. The timing, amplitude, and number of conver- phrenic patients in some positron emission tomography gent inputs is modulated by an extraordinary diversity flurodeoxyglucose (PET-FDG) studies would tend to fa- of extrinsic modulatory inputs including monoamine vor a hypoglutamatergic model (Buchsbaum et al. 1992; systems (Goldman-Rakic et al. 1990) and thalamocortical Tamminga et al. 1992). However, PET-FDG of resting glutamatergic projections (Carlsson et al. 1997). Also, metabolism in schizophrenic patients have been incon- within a particular cortical region, local circuits involv- sistent in their findings (Weinberger and Berman 1996). ing the interplay of glutamatergic and GABAergic neu- PET-FDG and [1H]-MRS studies also have provided di- rons are critically important for maintaining the opti- rect or suggestive evidence of a prefrontal hypermeta- mum capacity to process information (Wilson et al. bolic and hyperglutamatergic pathological process in 1994). The integrity of the interplay of these multiple schizophrenia (Bartha et al. 1997; Cleghorn et al. 1989). mechanisms is reflected by several indices including Furthermore, even when a group of patients shows de- high-frequency electrical activity (40 Hz) (Wang and pressed frontal metabolic activity, psychotic symptoms Buzsaki 1996). are frequently associated with increases in metabolism The seeming paradox that subanesthetic ketamine (Cleghorn et al. 1990; Tamminga et al. 1992). For the lat- activates prefrontal cortex metabolism and yet substan- ter studies, the combination of hypermetabolism and tially blunts the cognitive activation of this region may cognitive activation deficit supports the model growing reflect the disruption of inhibitory neurotransmission from effects of NMDA antagonists on the function of by subanesthetic ketamine. Both in the hippocampus cortical circuits. If all of these studies are valid, the clin- and in the cerebral cortex, low-dose NMDA antagonists ical literature suggests at least two possible interpreta- may preferentially disrupt feedforward and feedback tions: (1) schizophrenic patients, are more variable in activation of GABAergic interneurons (Grunze et al. their glutamatergic regulation than controls; that is, 1998; Lisman et al. 1998). These models predict that dis- some patients are hypoglutamatergic and others are hy- inhibition produces a loss of adaptive functional modu- perglutamatergic; or (2) individual patients have defi- lation or “tuning” of glutamatergic activity within a region. cits in their capacity to “tune” their cortical glutamater- In other words, deficits in NMDA-receptor function pro- gic function optimally and, therefore, they seem to be duce an inappropriate recruitment of additional neu- hypoglutamatergic or hyperglutamatergic, depending rons, may extend the duration of activation, may cause upon state-related factors. The latter possibility is at- disproportionate (abnormally large or small) magni- tractive, because it may highlight the potential role of tude of activation to the input, and reduced capacity to GABA, , and neuropeptide systems in terminate one response to process the next input. The optimizing cortical information processing (Aghajanian consequence of NMDA-mediated disruptions within and Marek 1999; Arnsten 1997; Jakab et al. 1997; Wil- local circuits may be loss of region-specific associative liams and Goldman-Rakic 1995; Wilson et al. 1994). functions, such as “stimulus-binding” in the hippocam- Cortical disturbances in schizophrenic patients may pus or working memory in the prefrontal cortex (Grunze or may not be related to changes in NMDA receptors. et al. 1998; Lisman et al. 1998). For example, there may be functional similarities be- A network-based view of NMDA-antagonist effects tween deficient cortical feedback inhibition predicted to may have important implications for the so-called exist in schizophrenia on the basis of postmortem evi- “NMDA-antagonist model of schizophrenia.” First, it dence (Akbarian et al. 1993; Akbarian et al. 1995; Benes suggests that NMDA-antagonist effects may resemble et al. 1991; Woo et al. 1998) and the disinhibiting effects cortical dysfunction associated with schizophrenia, be- of NMDA antagonists. Second, in schizophrenic pa- cause both conditions are associated with similar im- tients, many distinct neurobiological abnormalities could pairments in the information-processing capacity of produce convergent functional disturbances in cortical cortical circuits. However, several neural network models networks. Thus, circuit models would not be inconsis-

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tent with the existence of heterogeneity in the etiology when used as an , is generally adminis- or pathophysiology of schizophrenic patients. Third, if tered chronically before clinical benefits are observed. schizophrenia is associated with NMDA-antagonist– Together, these data question the centrality of dopa- like disturbances in the function of cortical networks mine to the positive and negative symptoms associated and not actual deficits in NMDA-receptor function, then with the NMDA antagonist psychosis. They may also putative pharmacotherapies growing out of the NMDA have implications for the applicability of NMDA antag- antagonist model may or may not apply to the treat- onist effects for schizophrenia. NMDA antagonists do ment of schizophrenia. Thus, candidate therapies grow- not produce an amphetamine-sensitive psychosis. Thus, ing out of this model will need validation in treatment effects of NMDA antagonists differ studies conducted in patients. from the hyperdopaminergic pathophysiology of pa- tients who respond well to typical neuroleptics. Psycho- stimulants produce a range of responses from improve- THE ROLE OF DOPAMINE IN THE ment to exacerbation in psychosis in patients (Lieberman NMDA-ANTAGONIST MODEL OF PSYCHOSIS: et al. 1987a). Those patients who show worsening tend IMPLICATIONS FOR THE RELEVANCE OF to have greater activation of dopamine systems follow- NMDA ANTAGONISTS TO SCHIZOPHRENIA ing amphetamine (Laruelle et al. 1996). The hypothesis that NMDA antagonist effects are most relevant to pa- To date, no compelling clinical data implicate dopa- tients with a poor prognosis when treated with typical mine in the positive or negative symptoms produced by neuroleptics is consistent with the symptom profile NMDA antagonists in healthy subjects or schizophrenic produced by ketamine in healthy subjects. Rather than patients. Studies of animal behavior question the cen- producing a pure paranoid state, the prominent but trality of NMDA-antagonist effects on dopamine sys- transient negative symptoms, thought disorder, and tems to many of the behavioral effects of these drugs cognitive deficits associated with ketamine administra- (Carlezon and Wise 1996; Carlsson et al. 1997; Keith et al. tion may have greatest relevance to “nonparanoid” 1991). In healthy subjects, acute pretreatment with 5 mg patients who exhibit prominent levels of symptoms and of haloperidol, 25 mg of clozapine, and 5 mg of olan- cognitive deficits in a spectrum of symptomatic and zepine did not significantly reduce positive or negative functional domains (Carpenter et al. 1988; Keefe et al. symptoms produced by NMDA antagonists (Krystal et al. 1996). 1999b; Lipschitz et al. 1997). The findings with typical However, clinical research has made little progress neuroleptics in healthy subjects are consistent with the to date in studying the potential unique contributions view that chronic treatment with typical neuroleptics is of non–D2-dopamine receptors to the cognitive and be- ineffective in reducing the effects of ketamine in schizo- havioral effects of NMDA antagonists. Clearly, D1/D5 phrenic patients (Lahti et al. 1995b; Malhotra et al. receptors play important modulatory roles in local cor- 1997). However, chronic treatment with atypical neuro- tical circuits in the prefrontal cortex (Williams and leptics may be superior to typical neuroleptics in blocking Goldman-Rakic 1995). A role for D1/D5-dopamine re- ketamine effects, although they are still quite limited in ceptors in modulating ketamine effects may be consis- this regard (Malhotra et al. 1997). tent with the fact that both haloperiodol, which blocks

Consistent with preclinical studies (Verma and Mog- D2/D4 receptors (Lévesque et al. 1992; Van Tol et al. haddam 1996), haloperidol pretreatment prevented ket- 1991), and amphetamine, which causes the stimulation amine-induced deficits in higher cortical functions in of all dopamine receptors, reduce aspects of the behav- healthy human subjects (Krystal et al. 1999b). Although ioral effects of ketamine. Thus, the contributions of D1/D5 haloperidol and ketamine produced additive impair- receptors to the behavioral effects of ketamine and the ments in attention, haloperidol pretreatment attenuated signs and symptoms of schizophrenia remain of scien- the impairments in abstract reasoning, as measured by tific and clinical interest. proverb interpretation, and abstract problem solving, as measured by the WCST. Amphetamine pretreatment also failed to exacerbate psychosis or negative symptoms in healthy subjects ad- THERAPEUTIC IMPLICATIONS OF THE ministered ketamine (Krystal et al. 1998c) although am- HYPERGLUTAMATERGIC EFFECTS OF phetamine seems to increase the stimulatory effect of NMDA ANTAGONISTS ketamine on mesostriatal dopamine systems in humans (Kegeles et al. 1999). The observation that amphet- This review highlighted several actions associated with amine-sensitive schizophrenic patients show a rapid in- subanesthetic doses of NMDA antagonists: reduction in crease in symptoms during amphetamine infusion NMDA-receptor function, distribution of pyramidal made this paradigm potentially more informative than neurons, and loss of functional regulation of activity of studies of acute haloperidol pretreatment. Haloperidol, pyramidal neurons. Each of these perspectives suggests

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novel pharmacologic approaches that might be evalu- though maintenance of normal glutamatergic function ated in schizophrenic patients. will be required to sustain cognition and behavior. The strategy of enhancing NMDA-receptor function Drugs that optimize extrinsic inputs to local cortical by augmenting treatment with an of the gly- circuits also could restore normal function. In this re- cine-B coagonist site of the NMDA receptor has re- gard, selective 5-HT2A-receptor antagonists are of inter- ceived the greatest study to date. One preliminary re- est. In rat PPI studies, selective 5-HT2A antagonists and port suggests that intravenous glycine infusion, at doses atypical neuroleptics with potent 5-HT2A antagonism that raise human cerebrospinal fluid levels by up to seem to be more effective than typical neuroleptics in fourfold, attenuates some behavioral effects of ket- preventing PCP-related disruption of sensory gating amine in healthy human subjects (D’Souza et al. 1997). (Kehne et al. 1996; Swerdlow and Geyer 1998; Varty et

This finding is consistent with evidence that chronic ad- al. 1999). Also, 5-HT2A antagonists and atypical neuro- ministration of very high oral doses of glycine and low leptics seem to be more potent than D2 antagonists in doses of the D- may produce blocking the stimulatory effects of NMDA antagonists reduction in negative symptoms, improvement in on locomotor activity and limbic dopaminergic activity mood, and improvement in attention and problem- (Gleason and Shannon 1997; Martin et al. 1997; Schmidt solving (Goff et al. 1995, 1999; Heresco-Levy et al. 1999; and Fadayel 1996). Similarly, the possibility that cloza- Javitt et al. 1994; Leiderman et al. 1996). Recently, prom- pine may be more effective than haloperidol in prevent- ising data were published regarding the addition of ing symptomatic exacerbation in patients administered

D- to neuroleptics (Tsai et al. 1998). These data ketamine draws attention to 5-HT2A-receptor mecha- suggest that enhancement of NMDA-receptor function nisms (Malhotra et al. 1997). It is not yet known may produce benefits in schizophrenic patients. How- whether selective 5-HT2A antagonists reduce ketamine ever, for unclear reasons, benefits of glycine-B agonists effects in humans. As noted earlier, serotonin and sero- may not be observed when added to clozapine (Goff et tonergic activate layer V cortical glutamate al. 1996). There is also great interest in studying the neurons (Aghajanian and Marek 1999). Thus, the capac- clinical efficacy of glycine transporter antagonists in hu- ity to produce innappropriate (i.e., not driven by sen- man laboratory paradigms and treatment of schizo- sory input) cortical glutamatergic activation is common phrenic patients (Javitt et al. 1997). to both hallucinogens and NMDA antago- A second pharmacologic strategy growing from the nists (Krystal et al. 1998b). Consistent with this view, effects of NMDA antagonists is to attenuate “hyper- stimulatory effects of both serotonergic hallucinogens glutamatergic” states by drugs acting at metabotropic and PCP on cortical glutamate systems are reduced by glutamate receptors or voltage-dependent ion channels. the mGluR II/III agonist, LY354740 (Aghajanian and A preclinical study found that LY354740, an agonist at Marek 1999; Moghaddam and Adams 1998). Similarly, group II/III metabotropic-glutamate receptors (mGluR a 5-HT2A antagonist-reversible (M100907) component of II/III), attenuated PCP-stimulated enhancement of pre- the glutamatergic activation produced by NMDA an- frontal cortex glutamate release and cognitive impair- tagonists seems to arise from the capacity of NMDA an- ments in rats (Moghaddam and Adams 1998). Future tagonists to disinhibit raphe neuronal projections to the studies will evaluate LY354740 in schizophrenic patients cortex (Martin et al. 1998). Thus, like mGluR II/III ago- and in the human ketamine “model.” Another ap- nists, selective 5-HT2A antagonists may have the capac- proach has been to study the anticonvulsant, lamotri- ity to reduce or to “tune” glutamatergic activity. In con- gine. Lamotrigine attenuates some forms of cortical glu- trast to the neuroleptic–ketamine interactions cited tamate release via inhibition of sodium channels, P- and earlier, unpublished data suggest that low doses of

N-type calcium channels, and potassium channels (Grunze sertindole, which preferentially block 5-HT2A receptors, et al. 1998; Stefani et al. 1996; Waldmeier et al. 1996; attenuate the behavioral effects of ketamine in healthy Wang et al. 1996). Given the interaction of P- and human subjects (F. Vollenweider, unpublished data).

N-type calcium channels with NMDA receptors in cor- There is also suggestive evidence that selective 5-HT2A tical dendritic spines (Schiller et al. 1998), the interac- antagonists, such as M100907 (Offord 1998), or 5-HT2A/ tive effects of lamotrigine and ketamine were of inter- antagonists, such as amperozide (Bjork et al. 1992) or ri- est. In humans, lamotrigine attenuated the perceptual, tanserin (Miller et al. 1992; Wiesel et al. 1994) have effi- psychotic, and amnestic effects of ketamine in healthy cacy in schizophrenic patients. human subjects (Anand et al. 1997). The ability of LY354740 and lamotrigine to attenuate cognitive deficits highlights the importance of appreciating the nuances CLOSING OBSERVATIONS: GLUTAMATE AND of local circuit regulation. Drugs that prevent inappro- THE NATURAL HISTORY OF SCHIZOPHRENIA priate (i.e., abnormal neuronal recruitment or loss of the optimal temporal features of activity) or excessive This review highlighted the possibility that one parallel glutamate release may restore cognitive dysfunction al- between low-dose NMDA-antagonist effects and the

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pathophysiology of schizophrenia was their association This developmental view of glutamatergic contribu- with aberrant function of cortical circuits. Human neu- tions to schizophrenia raises a number of issues for fur- roimaging studies comparing schizophrenic patients ther study. First, it suggests that pharmacotherapies and healthy subjects are consistent in suggesting that that attenuate symptoms of schizophrenia by reducing when performing cognitive tests that activate the pre- hyperglutamatergic states may also have neuroprotec- frontal cortex in healthy subjects, schizophrenic pa- tive effects. These neuroprotective effects may be im- tients show cortical activation deficits (Weinberger and portant during the initial development of schizophrenia Berman 1996). With regard to the previous discussion, as well as during the period of exaggerated functional these activation deficits could be consistent with mod- decline in late life. Second, long-term benefits associ- els in which there is a glutamatergic deficit (i.e., no sig- ated with pharmacologic treatments for schizophrenia nal) or an inhibitory deficit in local circuit (i.e., no signal may include modulation of neurotrophic factors and above noise). other intracellular targets. Thus, these targets must be Glutamatergic hyperactivity and/or deficits in func- considered increasingly in medications development tional activation of glutamatergic neurons related to local for schizophrenia. Third, it is possible that the neuro- and distributed cortical networks may also have conse- protective aspects of treatment are unrelated to symp- quences for the natural history of schizophrenia. First, a tom control and that they must be considered as a dis- spectrum of developmental abnormalities attributed to tinct component of treatment. disturbances in programmed neural development or In closing, it is essential to stress that the line of re- the interaction of an aberrant developmental program search outlined in this review represents only one of with environmental insults have been described in many potential benefits stemming from the safe, cautious, adult schizophrenic patients (Raedler et al. 1998). Gluta- careful, and thoughtful utilization of NMDA antago- matergic disturbances, through loss of neurotropic ac- nists in clinical research. These agents have enabled in- tions of glutamate or exaggeration of neurotoxic effects vestigators to study aspects of the functional circuitry of glutamate, could contribute to abnormalities in neu- of the cerebral cortex. As a result, they provide a poten- ronal migration, dendritic regression, synaptic pruning, tial bridge to novel insights into the pathophysiology apoptosis, suppression of ongoing neurogenesis, and and treatment of schizophrenia. the enhancement of other regressive processes in neu- rodevelopment (Coyle 1996; Gage 1998; Komuro and Rakic 1993; Lipton and Kater 1989; Olney and Farber ACKNOWLEDGMENTS 1995a; Rakic et al. 1994). Thus, postmortem findings consistent with deficient neural connectivity in schizo- This review is based on a presentation to the symposium, “Is D2 phrenia could reflect glutamate-related abnormalities Antagonism Required for Antipsychotic Activity?” This sym- in both neurotrophic and neurotoxic functions in devel- posium was sponsored by Hoescht Marion Roussell, Inc. and held in Washington DC, February 17–18, 1999. The authors opment (Rajkowska et al. 1998; Selemon et al. 1998). En- thank Cameron Carter, M.D., Robert W. Greene, Ph.D., Gra- vironmental stresses (Bagley and Moghaddam 1997), ham Williams, Ph.D., Patricia Goldman-Rakic, Ph.D., Franz including neurotoxicity associated with viral infection Vollenweider, M.D., and Richard Mohs, Ph.D. for discussions (Fatemi et al. 1998), could contribute to the onset and related to elements of the presentation. The work described in exacerbation of symptoms via enhancement of cortical this review was supported by funds from the Department of Veterans Affairs to their Merit Review Program, Alcoholism and limbic glutamate release or its consequences. Research Center, Schizophrenia Biological Research Center, Similarly, there is a disproportionate rate and level and National Center for PTSD. It was also supported by the of cognitive decline among elderly schizophrenic pa- National Institute of Mental Health through Grants MH-30929 tients relative to age-matched controls (Davidson et al. and MH-44866 and by an unrestricted educational grant from 1995). Aging is associated with many regressive neu- Hoechst Marion Roussel. Dr. Krystal received additional fund- ing via an Independent Investigator Award from the National ronal developmental changes, which typically include Alliance for Research on Schizophrenia and Affective Disor- loss of dendritic arborization in pyramidal neurons in der, an award from the Patrick and Catherine Weldon Dona- layer V, but not layer IIIc (de Brabander et al. 1998). In ghue Medical Research Foundation, and the Civilian Defense one study (Rajkowska et al. 1998), schizophrenic pa- and Research Foundation. tients showed hypotrophic changes that included in- volvement of corticocortical projection neurons in layer IIIc. 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