New Approaches to the Drug Treatment of Schizophrenia

Gavin P. Reynolds and Carole Czudek Department of Biomedical Science The University of Sheffield Sheffield SIO ZTN, United Kingdom

New Approaches to the Drug Treatment of Schizophrenia

1. Introduction Schizophrenia is a disorder with a lifetime incidence of less than 1%, appearing in most sufferers during late adolescence or early adulthood. Combined with its chronic course, this makes the disease one of great social and economic impact. Since its description as a disease entity by Kraepelin at the end of the last century, and the introduction of the term “schizophrenia” by Bleuler shortly after, increased efforts have been made to identify treatment regimens that will control schizophrenic symptoms and allow the patient to return to a relatively normal life. However, many attempts at such treatment have, even in the past 50 years, been crude, ineffective, or associated with unacceptable side effects. Thus there are still elderly patients in our psychiatric hospitals who have, for example, undergone insulin coma or leucotomy. The history of modern antipsychotic drug treatment began in the early Advancer in Pharmacology, Volume 32 Copyright 8 1995 hy Academic Press, Inc. All rights of reproduction in any form reserved.

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1950s, which saw a revolution in psychiatric care with the introduction of chlorpromazine, the first therapeutic agent with a specific action on

schizophrenic symptoms. There is no doubt that chlorpromazine, the other phenothiazines, and the related compounds that were developed over the following decade or so have brought about a major advance in the treatment of schizophrenia. This drug treatment is, however, not without its own problems. Antipsychotic action occurs in conjunction with deleterious side effects, most notably parkinsonism, dyskinesias, and akathisia. These extrapyramidal symptoms were then considered by some to be a necessary concomitant to the antipsychotic efficacy of these drugs and led to their being described as “neuroleptic.” [This review employs the term “antipsychotic” to describe a drug effective in the treatment of (some symptoms of) schizophrenia. While antipsychotic is not an ideal description, it is less awkward than “anti-schizophrenic’’ and far more meaningful than “neuroleptic”]. It is now apparent that undesirable motor or other side effects are not required correlates of antipsychotic action and in fact may reduce the acceptability of treatment and hence patient compliance. This provides one rationale for the identification of improved antipsychotic drugs. Two further limitations of current drug treatment of schizophenia have expanded the search for more specific and more effective antipsychotics. The first problem is that 20-30% of patients do not respond adequately to treatment with the classical antipsychotic drugs. Another problem, to some extent related to this poor response, is that the classical antipsychotic drugs are more effective at ameliorating some disease symptoms than others (Table I). The symptoms of schizophrenia may vary greatly between patients; in fact, no single core symptom is seen in all patients. The variability in8ymptom profile has led to the classification of subtypes of the disease, with implications in terms of differences in etiology or pathology. Thus Crow (1980) has defined two syndromes on the basis of the relative proportions of positive or negative symptoms. This does not imply that the categories are entirely distinct; patients may show overlap between the two types and may change symptoms, and hence syndrome, during the course of the disease. Recently, a more systematic study has defined three discrete syndromes: reality distortion, psychomotor poverty, and disorganization (Liddle, 1987), a classification for which others have also found evidence. These disease subtypes have neuroanatomical correlates, but as yet no systematic study TABLE I Major Limitations of Treatment with Classical Antipsychotic Drugs Unwanted side effects Inadequate response in some patients (“nonresponders”) Poor effect on negative symptoms

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of their relationship to antipsychotic drug response has been made, although this would be invaluable in understanding the relationships among psychopharmacology, neuropathology, and phenomenology in schizophrenia. Nevertheless the more simple positive-negative symptom dichotomy has proven useful in identifying symptoms that do not respond as well as some to classical antipsychotic drug treatment. These are the negative symptoms; their effective treatment is the third target for modern antipsychotic drug development. Concurrent with ongoing pharmacological research, recent work is beginning to shed light on the abnormalities that are present in the brain in schizophrenia. The application of quantitative histopathological techniques and the development of methods for brain imaging have provided evidence for a neuropathology of schizophrenia (reviewed by Roberts, 1991), while postmortem neurochemical studies have also indicated the involvement of neurotransmitter systems in this pathology (Reynolds, 1989). Although these findings have already provided pointers toward potential antipsychotic mechanisms, there is still a way to go before psychopharmacological research draws substantially from such pathological studies.

II. The Dopamine Hypothesis As analytical neurochemical techniques developed in the 1950s and 1960s, new putative neurotransmitters and other potentially psychoactive compounds were identified in the brain. Inevitably this led to several new hypotheses regarding the etiology of schizophrenia. But it was a combination of clinical observation and neuropharmacological studies that provided the evidence on which the dopamine hypothesis of schizophrenia was established. This hypothesis, which remains the basis both for the understanding of antipsychotic drug action and for the development of new antipsychotics (see Section 111), originally developed from the observations that high doses o r chronic administration of amphetamine to humans can induce a psychosis indistinguishable from acute paranoid schizophrenia (Randrup and Munkvad, 1965). Amphetamine acts by increasing dopamine release; other dopamine agonists may also have similar psychotogenic effects. Further support was provided by the finding that antipsychotic drugs block dopamine receptors and, although other neurotransmitter receptors may also be affected by these drugs, it is their antagonist action at the D2subtype of dopamine receptors that correlates particularly well with their clinical efficacy (Seeman et al., 1976). Interest in the dopamine hypothesis received a substantial stimulus in the late 1970s when it was discovered that there was an increase in the numbers of D2 receptors in brain tissue taken postmortem from schizo-

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phrenic patients (Owen et al., 1978). Some years of dispute followed over the origin of this increase in receptors: was it related to the disease process or was it an effect of prior drug treatment? Drugs blocking D2 receptors induce, after some weeks administration, an up-regulation of D2 receptor density (Clow et al., 1980), and it was argued that the antipsychotic treatment inevitably received by most schizophrenic patients was responsible for the increase in brain D2 receptors (Reynolds et al., 1981). The introduction of positron emission tomography (PET) imaging studies had been expected to provide a consistent answer to this problem by permitting assessment of radioligand binding to dopamine receptors in untreated living patients. The first major PET study of neuroleptic-naive patients reported a D2 receptor increase (Wong et al., 1986); this finding was, however, not confirmed by other groups (e.g., Farde et al., 1987) and, following further studies, many now accept that the increase in D2 receptors is primarily a response to drug treatment and probably does not occur in young, untreated schizophrenic patients. The many biochemical studies of the past 20-30 years have provided no conclusive evidence to support a general overactivity of dopamine neurons in schizophrenia. The major dopaminergic innervation in the brain is the nigrostriatal system, primarily concerned with motor function, and this system is essentially unaffected in the disease. More strongly implicated are the mesocortical and mesolimbic dopamine pathways; these innervate regions of the brain concerned with attention, mood, social interaction, and various other complex behavioral functions that may be disturbed in schizophrenia. Since a role for dopamine systems in antipsychotic drug action remains strongly indicated, the major approaches to drug development have primarily concentrated on compounds that either directly or indirectly reduce the activity of limbic dopaminergic synapses. Postmortem studies of the brain in schizophrenia have provided substantial evidence for neuronal abnormalities in the regions of the limbic system in the medial temporal lobe: the amygdala, hippocampus, and parahippocampal gyrus. This has primarily emerged from neuropathological investigations over the past decade, which have been extensively reviewed elsewhere (Roberts, 1991). Several neurochemical changes have been identified in these brain regions that presumably reflect neuronal deficits or dysfunction; these include diminished concentrations of markers for glutamatergic and GABAergic neurons and reduced density of certain glutamate receptors. The only direct evidence for a dopaminergic abnormality, however, is an increase in dopamine concentrations in the amygdala (Reynolds, 1983), an effect that occurs primarily in the left hemisphere, where several other studies, both morphological and neurochemical, report more severe abnormalities. It seems likely that this change may also be secondary to neuronal deficits. Thus the correlation found between the loss of hippocampal GABA neurons and the increase in dopamine concentrations in the left amygdala implies

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that the neurons lost in schizophrenia could result in a hyperactivity of dopaminergic neurons (Reynolds et al., 1990). Such an interpretation is highly speculative but provides a much needed mechanism whereby dopamine antagonist drugs might ameliorate some of the consequences of neuronal deficits in schizophrenia. It is certainly arguable whether the action of antipsychotic drugs in the treatment of schizophrenia is simply and solely due to a postsynaptic blockade of hyperactive dopamine systems. The improvement in symptoms following drug treatment is a process that occurs usually over a period of weeks; this does not parallel the time course of receptor blockade which occurs within hours. Attempts to understand this discrepancy have relied on the changes in dopamine metabolism that are brought about by the drugs. Dopamine turnover increases following D2receptor blockade but, after some time, a tolerance develops in which this initial increase in metabolism returns to normal. The magnitude of this effect varies between different brain regions, with the greatest tolerance developing in the amygdala and the least in the frontal cortex (Matsumoto et a/., 1983). Thus it has been suggested that the continued increase in metabolism in the frontal cortex is important in the antipsychotic effect (Bacopoulos et al., 1979). However, the opposite argument has also been proposed: the reversal of the increase in dopamine metabolism in the amygdala, a region of the limbic brain, might relate to the antipsychotic response (Kilts et al., 1988). This is consistent with some observations on the relationship between blood concentrations of the dopamine metabolite homovanillic acid (HVA) and the clinical response to drug treatment. A decrease in plasma HVA correlates with an improvement in clinical symptoms following treatment with antipsychotics (Pickar et al., 1984); since plasma HVA derives in part from subcortical brain dopamine, it is conceivable that this change reflects the development of tolerance to dopaminergic blockade in striatal and limbic brain regions.

111. Animal Behavioral Models for the Identification of Potential Antipsychotic Efficacy A. Dopaminergic Effects on Motor Function

The dopamine hypothesis of schizophrenia has provided the basis for what in the past have been the most commonly used animal tests for the assessment of potential antipsychotic drugs. These tests are based on the effects of dopaminergic agonists, such as apomorphine, or dopaminereleasing drugs, such as amphetamine, on certain motor behaviors. These behaviors, which include stereotypy, locomotor activation, and climbing behavior, to some extent have anatomical correlates. Thus locomotor activation induced by apomorphine or amphetamine is a measure of mesolimbic

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dopaminergic function, being induced by direct injection of agonist into the nucleus accumbens, while stereotyped behavior reflects striatal dopaminergic function. Both empirical and theoretical considerations have led to drug action at the former site, considered a model for antipsychotic efficacy, while effects on striatal dopamine-mediated behaviors are thought to indicate the propensity to induce extrapyramidal side effects (reviewed by Iversen, 1986). The antipsychotic drugs also have direct effects that model the motor side effects of treatment. Acute administration can induce both catalepsy in rats and dyskinesias in dogs, correlates respectively of parkinsonism and akathisia, while chronic treatment may cause dyskinetic movements in primates analogous to tardive dyskinesia (Gunne et al., 1984). Simple dose-related separation of effects on limbic behaviors from effects on these indicators of striatal dopaminergic dysfunction provides a means of identifying potential antipsychotic drugs with fewer extrapyramidal side effects. Thus the benzamides sulpiride and remoxipride, as well as clozapine and thioridazine, are more effective at blocking the hyperactivity than the stereotypy induced by apomorphine (by factors of 3.7, 7.2, 2.6, and 2.0, respectively), while the classical antipsychotics chlorpromazine (1.3) and haloperidol (1.0) do not discriminate these behaviors (Ogren et al., 1990). Similarly, the separation in dose between apomorphine-induced hyperactivity blockade and catalepsy provides a valuable indicator of low extrapyramidal side effects in an antipsychotic drug (Gerlach, 1991). More specific approaches to the induction of limbic dopaminegic hyperactivity have employed direct injection of amphetamine, or dopamine itself, into the terminal regions of the mesolimbic dopaminergic pathway (Costall et al., 1990). Thus bilateral injection of amphetamine into the nucleus accumbens induces acute hyperactivity, which can be blocked by prior injection of classical antipsychotic drugs, as well as by some nondopaminergic candidate drugs. A chronic dopaminergic hyperfunction characterized by occasional peaks of hyperactivity can be induced by persistent infusion of dopamine (over 13 days) into the accumbens (bilaterally) or the amygdala (unilaterally, to the subdominant hemisphere) (Costall et al., 1990). These behaviors can also be inhibited by both classical antipsychotics and other compounds in development as antipsychotics, including 5-HT3 antagonists (see Section 1X.B). As models of schizophrenia, such drug-induced motor behaviors have substantial limitations. One is that increased motor function is not usually observed in unmedicated schizophrenic patients; it is certainly not a core symptom. Another limitation is the reliance on dopaminergic mechanisms, which inevitably restrict the pharmacological profile to drugs that, directly or indirectly, decrease dopaminergic function. Attempts to model more closely aspects of abnormal behavior in schizophrenia, as well as to break away from drug-induced dopamine-mediated effects, have resulted in alternative paradigms. One test which relies on a direct cognitive behavioral effect of the drugs under investigation is the conditioned avoidance response (CAR).

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6. Conditioned Avoidance Response The ability of a compound to inhibit a CAR is now a common behavioral procedure used to screen new antipsychotic drugs (Cook and Davidson, 1978), and it has been demonstrated that there is a high correlation between disruption of CAR performance and clinical antipsychotic potency (Kuribara and Tadokoro, 1981). CAR is an active-avoidance behavior in which an animal learns a response in order to avoid a noxious stimulus (typically an electric foot shock). Two kinds of response are usually measured in CAR: escape responses, which are caused by the shock itself, and avoidance responses, which are elicited by a conditioned stimulus, such as a light or tone that precedes the shock by a few seconds. An animal can escape from the shock by, for example, moving from one shuttlebox compartment to another, releasing a lever, or climbing a pole. The animal also learns that the shock can be avoided by performing the same behavior in response to the conditioned stimulus. Antipsychotic drugs impair avoidance behavior without affecting escape behavior, although at high doses the escape latency may also be affected. Ideally, therefore, antipsychotics should have a good separation between the doses required to inhibit escape and avoidance responses. This action of antipsychotics may be mediated via blockade of dopamine neurotransmission because CAR performance is disrupted by destruction of mesolimbic and nigrostriatal dopamine systems (Koob et al., 1984). The mesolimbic dopamine system is thought to be particularly implicated in this effect since CAR is inhibited by direct injection of the D2 antagonist sulpiride into the nucleus accumbens and not the striatum (Wadenberg et al., 1990). Although this behavioral model is widely used as a screen for antipsychotic activity, it has, however, been suggested that it may more accurately be a test for extrapyramidal side effects (Ahlenius, 1979), based on the fact that anticholinergics, used to treat such side effects, are able to antagonize the antipsychotic-induced inhibition of avoidance behavior. Arguing against this are reports that inhibition of CAR is a property that is shared by classical antipsychotic drugs, “atypical” antipsychotics, such as clozapine, and some putative antipsychotics (Egbe et al., 1990; McQuade et al., 1991; White et al., 1991a). CAR does not, however, provide a model for schizophrenia but is simply an heuristic assessment of antipsychotic drug action. More recent approaches have employed latent inhibition or prepulse inhibition as potentially more valuable behavioral paradigms since they are also disrupted in schizophrenic patients.

C. Latent Inhibition Latent inhibition (LI) refers to the interference that exposure to a stimulus has on subsequent conditioning to that stimulus (Ludlow, 1973). It is disrupted in acute schizophrenia (Baruch et al., 1988),in which it is indicative of disorders of attention and information processing, and it can be abolished

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in animals by low dose amphetamine, an effect that is reversed by haloperidol (Weiner et al., 1990). LI is thought to involve nucleus accumbens, but not striatal, dopamine systems, on which low doses of amphetamine preferentially act; this is supported by evidence from regionally specific intracerebral injection of amphetamine. A simpler paradigm with similarities to LI is prepulse inhibition of the startle reflex (PPI), a phenomenon occurring on first testing in mammalian species that thus does not require the training needed for assessment of LI. D. Prepulse Inhibition of the Startle Reflex The startle reflex is a skeletomuscular response that occurs after presentation of strong acoustic, tactile, and other stimuli (Davis, 1984). In rats this reflex can be accurately quantified by measurement of whole body jump, normally after a loud noise. In humans, the eye blink component of the startle reflex provides a reliable index of the response. If a weak prestimulus, such as a low-density tone or light, is presented shortly before the startle stimulus, then the magnitude of the startle reflex decreases. This PPI is an indication of sensorimotor gating. Schizophrenic patients exhibit a deficit of PPI (Braff et al., 1992), and it has been suggested that they are incapable of screening out irrelevant sensory information and thus experience “sensory flooding” (McGhie and Chapman, 1961). A decrease in PPI in rats can be produced by administrating apomorphine or amphetamine, which may thus provide an animal model of the sensorimotor deficits in schizophrenia (Mansbach et al., 1988; Davis et al., 1990). Antipsychotic drugs reverse this decrease in PPI indicating the potential of the model for the screening of candidate antipsychotics (Swerdlow et al., 1991). The neuronal circuitry that appears to be involved in sensorimotor gating includes a corticostriato-pallidal-thalamic circuit, which connects the limbic and striatal systems (Swerdlow and Koob, 1987). Dopamine agonist disruption of PPI is mediated via D2 receptor activation in the nucleus accumbens (Geyer et al., 1990; Swerdlow et al., 1986).The limbic system is particularly implicated since intraaccumbens administration of dopamine decreases PPI (Swerdlow et al., 1990a). The classical antipsychotics haloperidol and chlorpromazine and the atypical drugs clozapine and risperidone block this decrease in PPI (Swerdlow et al., 1990b; Rigdon and Viik, 1991; Swerdlow and Geyer, 1993), while several anxiolytic or antidepressant drugs, among others, test negative in this paradigm (Rigdon and Viik, 1991). Interestingly enough, in the study by Swerdlow and Geyer (1993), clozapine also potentiated PPI in the absence of a dopamine agonist, an effect that on extrapolation is opposite to that seen in schizophrenic patients. These authors suggest that PPI might be capable of identifying antipsychotics without the need for prior administration of a dopamine agonist, which might avoid the bias toward the detection of dopamine antagonists of other animal models.

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E. The Hippocampal Lesion That there are neuroanatomical deficits in the brains of schizophrenic patients is increasingly apparent (reviewed by Roberts, 1991). If, as we might assume, this neuropathology is the etiological basis of schizophrenia, then equivalent anatomical lesions in animals should provide an optimal model of the disease. The hippocampus and its related structures, while not exclusively indicated as the site of neuropathology, do represent the anatomical focus of many biological and psychological investigations indicating neuronal dysfunction in schizophrenia. Schmajuk (1987)has reviewed and evaluated the evidence for hippocampally lesioned animals providing a model for schizophrenia, concluding that this model meets criteria relating to similarities with the disease in terms of behavior, neurobiology, and pharmacology. The latter was based on the effects of haloperidol on certain behaviors; however, no systematic study of a range of antipsychotics has been reported. Particularly interesting has been the observation that an excitotoxic lesion of the ventral hippocampus in neonatal rats can produce a dopaminergic supersensitivity (Lipska and Weinberger, 1993). This included both increased locomotor activity and stereotypy following apomorphine, the latter only becoming apparent after puberty, a finding with obvious analogies to the natural history of schizophrenia. Drawing on the evidence that the neuropathology of schizophrenia may be developmental in origin, Scheibel and Conrad (1993) suggest that certain genetic mutations in mice that express anomalies in hippocampal development provide models of the disease, at least in terms of anatomical abnormalities and dysgenesis. These two hippocampal lesions, exogenous and congenital, do have substantial potential in providing paradigms with greater relevance to schizophrenia and its treatment than do the purely behavioral, or pharmacobehavioral, models mentioned earlier. Moreover, as the neurochemical and neuropathological deficits that occur in schizophrenia are becoming better defined and understood, we can develop improved experimental models of the disease in the pursuit of more specific drug treatments.

IV. Dopamine D2Receptor Antagonists

A. Antipsychotic Effects and Extrapyramidal Symptoms Almost all drugs currently employed for the treatment of schizophrenia are dopamine D2 antagonists with general effects on brain dopamine systems. As previously mentioned, D, receptor blockade gives rise to a range of side effects of which the acute extrapyramidal symptoms (parkinsonism,

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akathisia, and dystonia) are more or less direct results of blockade of nigrostriatal dopamine receptors. The lower incidence of extrapyramidal effects associated with some drugs, such as thioridazine, has, in the past, been ascribed to a limbic selectivity. However, no such preferential affinity for limbic over striatal D2 receptors could be identified for this drug (Reynolds et al., 1982).Nevertheless, the identification by molecular cloning techniques of other DJike receptors with some differences in ligand affinities may serve to shed new light on the region-specific effects of antipsychotic drugs (see Section VII). Many of the antipsychotic drugs in current use have effects at other neurotransmitter receptors, and several of these actions give rise to unwanted side effects, incuding sedation, postural hypotension, and weight gain (Table 11). Such side effects can, of course, be avoided by compounds with a relatively specific dopamine D2 receptor antagonism. There is also an increasing recognition of patients’ subjective responses to antipsychotic drugs, which may include dysphoria, bradyphrenia, and a lack in concentration, motivation, and emotional response. This “neuroplepticinduced deficit syndrome” (Lader, 1993) probably relates to several different receptor effects and may be difficult to distinguish from negative symptoms. The introduction of specific D, antagonists may not be a particularly valuable approach to diminishing the incidence of extrapyramidal symptoms. Nevertheless, the highly selective D, antagonist sulpiride was one of the first drugs to offer a spectrum of action differing from the classical

TABLE II Some Common Side Effects of Antipsychotic Drug Treatment

Side effects

Proposed mechanism

Acute extrapyramidal symptoms Parkinsonism Akathisia Dystonia Tardive dyskinesia Weight gain Amenorrhea, galactorrhea

Dl receptor blockade

Impotence, ejaculatory dysfunction Sedation Postural hypotension Other autonomic effects, e.g., dry mouth, blurred vision

Not known (see text) 5-HT receptor blockade Hormonal effects induced by 5-HT, D2receptor blockade Hormonal effects: a,-adrenoceptor, D2 receptor blockade a,-Adrenoceptor, histamine receptor blockade a,-Adrenoceptor blockade Muscarinic receptor blockade

Note. In many cases the mechanisms remain to be fully elucidated and some drug-induced side effects (e.g., sexual dysfunction) are also far more complex than is suggested here.

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antipsychotics. Sulpiride has a lower incidence of parkinsonism, an effect predicted by its weak ability to induce catalepsy in animals (see Section 111). A related drug, the recently introduced, effective antipsychotic remoxipride, is also relatively selective for D, receptors and is also less likely to induce extrapyramidal effects than the classical antipsychotics; unfortunately, remoxipride treatment has recently been shown to be associated with hematological problems (e.g., Philpott et al., 1993). It is unclear why sulpiride and remoxipride should differ from the classical antipsychotics, although it may be that their somewhat lower relative affinities for the D, receptor permit more accurate titration of dose to an optimum level of receptor occupancy. Alternatively, the lower affinity of the substituted benzamides may impart some specificity to their action in uiuo, where they compete for endogenous ligand (i.e., dopamine) at the receptor site. PET imaging studies, as well as providing a means of measuring receptor density in uiuo in humans, can be used to assess receptor occupancy by drugs. This has been applied to antipsychotic occupancy of D, receptors, defined by radiolabeled raclopride, by Farde et al., (1992) who have shown effective drug treatment to be associated with over 70% blockade of striatal D, receptors (except in the case of clozapine, discussed in Section V). The incidence of extrapyramidal symptoms is, however, associated with levels of D, receptor occupancy of about 80% or higher, which commonly occur in treatment with classical antipsychotics, particularly haloperidol (Farde et al., 1992). This finding is consistent with clinical practice since parkinsonism will usually diminish on lowering the antipsychotic dose. Sulpiride and remoxipride have a D, receptor occupancy in the 70-80% range, consistent with their lower incidence of extrapyramidal side effects. The differences between sulpiride and the classical antipsychotic drugs, the phenothiazines and butyrophenones, have led to sulpiride being described as “atypical.” This term is now applied to any new potential antipsychotic and implies, often misleadingly, a lower incidence of extrapyramidal and other side effects. Sulpiride and a few other “atypical” antipsychotics have, however, an interesting specificity in their action on different dopamine pathways in the brain. While the classical antipsychotics will, after chronic administration, inhibit the activity of most dopaminergic neurons in the brain stem, “atypical” drugs only inhibit the A10 cells of the ventral tegmental area (White and Wang, 1983), the source of the mesolimbic and mesocortical projections. The A9 cells of the nigrostriatal pathway to the striatum are less affected by treatment with drugs such as sulpiride and clozapine. The mechanisms involved are not clearly understood, although differences in the feedback control of activity in these two groups of dopaminergic neurons are likely to be important. However, results obtained from freely moving animals have cast doubt on the validity of such electrophysiological studies as a model of dopaminergic activity (Andin et al., 1988).

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8. Tardive Dyskinesia One of the most serious side effects of antipsychotic drugs is tardive dyskinesia (TD), a syndrome involving abnormal involuntary movements and occurring after chronic treatment in approximately 30% of patients. The neuronal basis of this side effect remains obscure. The observation that D, receptor density is increased after chronic administration of several antipsychotic drugs provided the basis for the “dopaminergic supersensitivity hypothesis” of TD. However, neither postmortem studies nor in vivo PET imaging have indicated up-regulation of D, receptors in the striatum to be associated with TD, although a regionally specific increase in D, receptors has recently been identified in a postmortem study of TD (Reynolds et al., 1992). The effect was observed solely in the pallidum, the region of the brain particularly responsible for the generation of dyskinesias. Another model for the pathogenesis of TD is provided by Huntington’s disease, in which GABAergic deficits in the basal ganglia are fundamental to the production of dyskinesias; losses of markers for GABAergic neurons have been identified in both animal models and postmortem studies of the syndrome (Gunne etal., 1984; Anderson et al., 1989).It has been suggested that such neuronal damage may occur via free-radical mechanisms; the recent studies showing an improvement of tardive dyskinesia following administration of vitamin E (a free-radical scavenger) certainly support a (reversible) free-radical-induced neuronal dysfunction (e.g., Lohr et al., 1987). Both clozapine, with effects on many receptor systems (see Section V), and the D2-specific antagonists sulpiride and remoxipride are less likely to induce TD than are many of the classical antipsychotic drugs. This may conceivably relate to the fact that all three drugs have a relatively lower affinity for the D, receptor which, as mentioned earlier, may impart some specificity to their action in the brain. C. Partial D2Agonists

The development of D,-specific antagonists has proved useful in the treatment of schizophrenia, although this approach cannot completely eliminate the side effects associated with D2 blockade. An alternative way of attenuating dopamine neurotransmission is to minimize the release of dopamine through activation of presynaptic autoreceptors (Roth et al., 1987). It is generally accepted that dopamine synthesis and release are regulated by a negative feedback mechanism via D2-likedopamine autoreceptors (Stoof and Kebabian, 1984). These autoreceptors mediate the inhibitory effect of low doses of apomorphine on spontaneous locomotor activity (Di Chiara et al., 1978), while higher doses result in postsynaptic receptor stimulation and increased locomotor activity (Iversen, 1977). Electrophysiological studies confirmed that autoreceptors situated in the substantia nigra were 10-

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fold more sensitive to the inhibitory effects of dopamine and apomorphine than postsynaptic receptors in the striatum (Skirboll et al., 1979). These studies suggest that low doses of dopamine agonists might reduce dopaminergic function. The therapeutic potential of dopamine autoreceptor activation in schizophrenia was first suggested after the observation of apomorphine’s antipsychotic effect in acute psychosis (Smith et al., 1977; Corsini et al., 1977). However, symptom improvement was usually transient in nature and there was no therapeutic effect reported by other investigators (Angrist et al., 1980; Davidson et al., 1985; Ferrier et al., 1984). In the last few years a number of compounds have been synthesized that have a selective dopamine autoreceptor agonist profile in behavioral and in in vivo biochemical and electrophysiological models (for a review see Clark et al., 1985). These autoreceptor agonists are in fact partial D, agonists, which appear to have preferential affinity for autoreceptors. Such partial agonists acting at dopamine receptors can behave either as agonists or as antagonists depending on their intrinsic activity (Clark et al., 1985). Thus low intrinsic activity in a compound implies a low agonistic and therefore a high antagonistic effect, while high intrinsic activity results in a dopamine agonist effect. The exact reason for the dopamine autoreceptor selectivity of certain drugs remains unclear. Various explanations have been proposed, including differences in receptor “sensitivity” due, for example, to different amounts of receptor-coupling efficiency to second messenger systems, i.e., the receptor reserve, at pre- and postsynaptic receptors (Meller et al., 1987). Dopamine autoreceptors reportedly have a greater receptor reserve (Meller et al., 1987) than postsynaptic D, receptors (Meller et al., 1988; Clark et al., 1985). It is also thought that dopamine autoreceptors, unlike postsynaptic D2 receptors, do not require the simultaneous activation of D, receptors for expression of their full functional effect. Presynaptic inhibition of dopamine release via autoreceptors might lower dopamine concentrations to levels below those necessary for D, receptor activation and therefore remove the “enabling” actions of D, on D2 postsynaptic receptors. In addition, the suggestion that the newly identified D3 receptors may function as autoreceptors (see Section VII) provides an explanation for the pharmacological differences between pre- and postsynaptic D2-like receptors. The pharmacological effect of partial agonists is also determined by the degree of endogenous dopamine activity. When there is a high basal level of activity, antagonistic effects predominate and when there is a low level the opposite holds true. Thus, if hyperactive dopamine neurons exist in mesolimbic and mesocortical areas of the brain in schizophrenia (and are responsible for positive symptoms of the disease), then a partial agonist might selectively decrease dopaminegic tone in these areas without affecting normally functioning dopamine systems in other brain areas (e.g., the stria-

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turn), thereby eliminating the side effect profile seen with the neuroleptics after extensive dopamine receptor blockade. Several partial agonists have been tested in models predictive of potential antipsychotic action. Behavioral effects in these models resemble those of the classical antipsychotics in some respects. Preclamol [ (-)3PPP; Hjorth et al., 19831, terguride (Wachtel and Dorow, 1983; Kehr, 1984), and SDZ HDC-912 (Coward et al., 1988) block apomorphine-induced stereotypy. The degree of catalepsy caused by a partial agonist depends on its intrinsic activity. Preclamol and B-HT920 (talipexole) possess high intrinsic activity and do not induce catalepsy (Karobath et al., 1988; AndCn et al., 1982). Agonists with less intrinsic activity may produce catalepsy but at doses far higher than those required to inhibit apomorphine-induced hyperactivity (Coward et al., 1988). Thus it was suggested that autoreceptor agonists could ameliorate schizophrenic symptoms but would have a great advantage over typical neuroleptics in that they would be be free of extrapyramidal side effects. One potential problem would be a lack of specificity of the drug for the autoreceptor, with postsynaptic as well as presynaptic effects. Preclamol decreases dyskinetic movements without inducing parkinsonism in monkeys that had previously received long-term haloperidol (Haggstrom et al., 1983). This primate model, an experimental situation in which side effect liability might be more clearly predicted, has recently been used to test several partial dopamine D, receptor agonists for their extrapyramidal side effect potential (Peacock and Gerlach, 1993). SDZ HDC-912, SDZ HAC-91 1, and terguride all produce dystonia, whereas only SDZ HAC-911 suppresses oral hyperkinesia; other drugs exacerbate this correlate of acute dyskinesia. Several partial agonists have now been tested in human patients. Few of these compounds have shown unequivocal antipsychotic efficacy in wellcontrolled trials. Where patients were relatively free of parkinsonism, little in the way of clinical improvement was observed, while symptomatic improvement occurred in trials in which such extrapyramidal side effects were also induced. Thus in an open 4-week trial of SDZ HDC-912, many patients showed a good response with improvement in both positive and negative symptoms and in depressive mood (Naber et al., 1990). However, a mild degree of parkinsonism was also seen and, although a more recent placebocontrolled trial suggested that the drug did not induce any increase in extrapyramidal symptoms (Potkin et al., 1993), the drug is no longer in development due to the lack of any clear advantage over classical D, antagonism. Other dopamine partial agonists, including roxindole (Klimke and Klieser, 1991) and talipexole (Wiedemann et al., 1990), have proven less valuable in treating positive symptoms, which sometimes deteriorate, with associated psychomotor activation. In these studies, as with terguride (Olbrich and Schanz, 1988), clinical response was sometimes more apparent in the patients with negative symptoms. It is not clear that these (somewhat disappointing)

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clinical effects are solely due to specific actions at dopamine D, receptors. The drugs often have effects on other neurotransmitter receptors; roxindole also has 5-hydroxytryptamine (5-HT)uptake inhibiting and 5-HT1A agonistic actions (Seyfried et al., 1989) while talipexole has a2effects, and clearly these properties may contribute to the clinical actions of the drugs (see Sections IX and X). It appears that dopamine partial agonists may not be as therapeutically effective in schizophrenia as originally hoped. If molecular biological techniques allow presynaptic dopamine receptors to be better distinguished from other dopamine receptors (and this may well be the case; see Section VII), then development of a drug with selectivity at these sites might be an improvement over existing D, partial agonists.

V. Other Receptor Sites of Antipsychotic Action: The Clozapine Model Recent developments in potential antipsychotic treatments owe much to the pharmacology and clinical efficacy of clozapine (reviewed by Fitton and Heel, 1990). This drug was withdrawn shortly after its introduction as an antipsychotic in the 1970s following several fatalities because of druginduced agranulocytosis. Nevertheless, it had become apparent that clozapine offered a unique antipsychotic action, with an action on negative symptoms and a low incidence of extrapyramidal side effects and with a notable lack of tardive dyskinesia following long-term treatment. Perhaps the most important aspect of clozapine’s action (and, at present, its major clinical indication) is its efficacy in schizophrenic patients who do not respond to treatment with classical antipsychotics (“neuroleptic nonresponders”); approximately 50% of such patients demonstrate an improvement after 6 months of treatment with clozapine. A growing interest in its clinical potential has culminated in the recent reintroduction of the drug in several countries, where it is prescribed in conjunction with regular hematological monitoring of the patient to avoid the mortality associated with agranulocytosis. The pharmacological profile of clozapine contrasts strongly with the selectivity of sulpiride; its affinities for a,histamine, muscarinic, and several subtypes of 5-HT receptors all exceed that for dopamine sites (Table 111). This does not exclude its antipsychotic effect from involving an antagonist action at dopamine receptors, although PET studies show that in vivo it occupies approximately 50% of D, sites, somewhat lower than the 80% occupancy exhibited by classical antipsychotic drugs (Farde et al., 1992). Of the antipsychotics recently introduced or in development, olanzapine bears the closest resemblance to clozapine. Olanzapine has a D2 receptor affinity that is approximately 10-fold higher than clozapine, but similar

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TABLE 111 Affinity of Clozapine at Human Brain Neurotransmitter Receptors

Dopamine D, Dopamine D, Dopamine D, Dopamine D4 Serotonin 5-HT2 Serotonin 5-HTlA Noradrenaline al Noradrenaline a, Histamine H1 Acetylcholine M1

6.6

7.0 6.3-7.1 7.3-8.1 8.4 6.5 8.1 6.8 8.5 7.9

Note. Data adapted from Richelson and Nelson (1984),Reynolds (unpublished),and citations in text. Values in italics are from cloned receptors expressed in nonhuman cells.

affinities, with Ki values in the low nanomolar range, for the histamine H1, muscarinic M1, a,,and 5-HT2 receptors (Moore et al., 1993). It has a somewhat lower affinity for D,sites ( K i of 31 nM) than for D2 and substantially less effect at a2and 5-HT1A receptors. Ascertaining whether olanzapine shares clozapine’s ability to ameliorate the symptoms in a proportion of “neuroleptic nonresponders” will provide a major step toward understanding the pharmacological basis of this valuable clinical effect.

VI. Doparnine D, Receptors Dopamine receptors have been classified into D, and D, subtypes on a functional basis depending on whether they were positively linked ( D,) or independent or negatively coupled (Dz) to adenylate cyclase (Kebabian and Calne, 1979; Stoof and Kebabian, 1984). Several antipsychotic drugs, notably the thioxanthenes, have D, antagonist properties in addition to their D2 action, although clozapine demonstrates the greatest relative D, site occupancy in the clinic. This has been shown by in vivo PET studies of a radiolabeled D, antagonist in human brain (Farde et al., 1992); clozapine occupies 36-52% of D,sites. Flupenthixol may displace similar proportions of ligand from these sites, although this drug is associated with substantially higher D, receptor occupancy (Farde et al., 1992). When first identified, D, sites appeared to be less important than the

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D, receptors that mediate both antipsychotic and extrapyramidal effects. In the absence of selective ligands for the D,receptor, it was believed that no behavioral role could be ascribed to this receptor subtype since the behavioral characteristics of dopamine agonists and antagonists could be explained in terms of their interaction solely with D, receptors. With the introduction of the selective partial agonist SKF 38393 (Setler et al., 1978) and the selective antagonist SCH 23390 (Iorio etal., 1983), it soon became apparent that D, receptors do play a part in the mediation of dopaminergic behaviors. Although only a few characteristic behaviors can be ascribed to the D, receptor, it is clear that simultaneous stimulation of both D, and D, receptors is necessary for the complete expression of many dopamine-mediated behaviors and that D,receptors have a modulating or “enabling” function on D, receptors (Waddington, 1988). These synergistic effects relate to a functional and biochemical coupling and an anatomical colocalization of the two receptor subtypes, at least in the striatum (Surmeier et al., 1993). SCH 23390 replicates many of the actions of classical antipsychotics (including both those with selective D, antagonism and those also with D, effects) in a variety of behavioral paradigms that are predictive of antipsychotic potential. SCH 23390 antagonizes locomotor activity induced by amphetamine or apomorphine (Christensen et al., 1984; Molloy and Waddington, 1985; Schulz et al., 1985), attenuates apomorphine-induced climbing in mice (Gerhardt et al., 1985), and inhibits conditioned avoidance responding (Gerhardt et al., 1985). The drug is also active in the inhibition of the amphetamine cue in drug discrimination responding studies (Nielsen and Jepsen, 1985). Thus it was postulated that a highly selective D, antagonist might prove useful in the treatment of antipsychotic symptoms without having some of the undesirable side effects characteristic of the classical antipsychotics. For example, unlike the D2 antagonists, SCH 23390 does not increase prolactin release from the pituitary (Iorio et al., 1983), indicating that galactorrhea is unlikely to be a side effect of treatment with this drug. However, as well as the behavioral effects on dopamine systems just described, D,antagonists can induce behaviors predictive of extrapyramidal symptoms. SCH 23390 antagonizes the stereotyped behavior produced by dopamine agonists in rodents (Molloy and Waddington, 1984; Mailman et al., 1984) and induces catalepsy (Christensen et al., 1984; Morelli et al., 1985). This is certainly suggestive of a liability to induce parkinsonism, and this side effect has indeed been observed after systemic administration of SCH 23390 to African green monkeys (Lawrence etal., 1991). Other experiments in primates, which inevitably provide a better indication of the risk of extrapyramidal side effects associated with treatment in humans, have not always been consistent. In previously drug-naive Cebus monkeys, chronic weekly oral dosing of SCH 23390 did not lead to abnormal movements,

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an effect that was true of haloperidol or raclopride administration (Coffin et al., 1989). Gerlach and Lublin (1988) have also demonstrated that an oral dose of 10 mg/kg SCH 23390 had no effect on the induction of abnormal

movements, although this was not the case after subcutaneous administration. There has been speculation as to whether the bioavailability of oral SCH 23390 may be responsible for its lack of production of extrapyramidal effects (Casey, 1992). Dystonia has also been induced in monkeys by SCH 23390 administration (Kistrup and Gerlach, 1987; Casey, 1992). However, the D, antagonist N N O 756, in increasing doses, was unable to induce dystonia in drug-naive monkeys, while parkinsonism was observed (Hansen and Gerlach, 1991). Nevertheless, these extrapyramidal symptoms may disappear on chronic administration as tolerance develops (Christensen, 1990; Gerlach and Lublin, 1988). D, antagonists have also been investigated for their action on extrapyramidal movements in haloperidol-treated primates. SCH 23390 potentiates haloperidol-induced dyskinesias (Gerhardt et al., 1985). The effects of chronic subdystonic dosage with SCH 23390 or the selective D, antagonist raclopride were recently investigated in monkeys withdrawn from haloperidol. This resulted in dystonic attacks, bradykinesia, catalepsy and sedation, and decreased locomotor activity with both drugs, although only the animals treated with SCH 23390 developed tolerance to dystonic attacks (Lublin et al., 1993). A study in five haloperidol-primed Cebus monkeys has shown the reversal of extrapyramidal side effects by SCH 39166 (McHugh and Coffin, 1991). However, the neuroleptic-primed monkey may actually be a poor predictor of human dyskinetic side effects (Waddington, 1988). SCH 39166 is currently undergoing clinical trials, and only after this drug and other structurally diverse selective D1 antagonists have been chronically administered to humans will an unequivocal answer be obtained as to the potential of these drugs for the induction of extrapyramidal side effects and tardive dyskinesia. From these studies one cannot conclude whether the D, antagonism of clozapine is likely to make an important contribution to its unique clinical profile. Nevertheless, it is conceivable that, with clozapine and other such mixed D,/Dz antagonists, a synergism between the D1 and D, blockade might induce an antipsychotic response without reaching the threshold for the appearance of extrapyramidal effects. Certainly other mixed D,/D, antagonists are in development. SDZ DOD-647 has a greater affinity for the D, than the Dz receptor (by a factor of eight) and thus shows greater relative selectivity for D, than clozapine. Like clozapine, it is effective in some models predictive of antipsychotic potency but does not induce catalepsy in rats (Markstein et al., 1993) and thus is considered a suitable candidate for development as an antipsychotic.

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VII. Dopamine D3and D4Receptors Recently, molecular biology (otherwise somewhat of a disappointment in its application to the genetics of schizophrenia) has provided a new perspective in which to consider antipsychotic drug action. In 1990, a new dopamine receptor, termed D,, was discovered by cloning following the identification of its mRNA (Sokoloff et al., 1990). In comparison to D,, D, generally has a higher affinity for dopamine and other agonists but a slightly lower affinity for most antagonists. Unlike the D, receptor, found primarily in the striatal regions of the brain, the D, receptor is expressed mainly outside the striatum, notably the mesolimbic terminal regions of the nucleus accumbens and olfactory tubercle. Since the antagonist pharmacology of D, resembles that of D,, it has been suggested that this D3 receptor may be more important in mediating antipsychotic drug action, while blockade of the D, receptor is primarily responsible for extrapyramidal symptoms. The presence of D3 receptor mRNA in the substantia nigra suggests that D, may have some autoreceptor function (Sokoloff et al., 1990); its higher affinity for dopamine agonists is notable in the light of the higher sensitivity of autoreceptors for dopamine and apomorphine (discussed in Section 1V.C). The study of the D3 receptor is hampered by the low amounts of the protein in brain tissue; however, determination of its mRNA has yielded some interesting results supporting its proposed role in antipsychotic mechanisms. As would be expected, mRNA for D, is increased following classical antipsychotic drug administration. This is also true to a greater extent for D, although, unlike D,, D3 mRNA is also increased following high doses of sulpiride and clozapine (Buckland et al., 1992, 1993). How closely these findings are parallelled by changes in receptor density has yet to be determined. Genes for two further dopamine receptors have now been identified. D, is another D,-like receptor while D, is more closely related to D,.The D, receptor resembles the D, and D3 proteins with approximately 40% homology and is expressed in regions that include the amygdala and frontal cortex (Van To1 et al., 1991), parts of the brain implicated in the functional pathology of schizophrenia. Furthermore, its potential importance in antipsychotic action is particularly indicated by the fact that clozapine is reported to have a 15-fold greater affinity for D, than for the Dz site, while other antipsychotic drugs generally have a preference for D,. Seeman (1992) has pointed out that while therapeutic levels of most antipsychotics lead to substantial D, receptor blockade, clozapine alone has a low occupancy of D, sites while blocking most D4receptors. This is certainly consistent with the interpretation that clozapine’s efficacy is due to D, receptor blockade. It is less clear whether the strong correlation between therapeutic availability

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and D2 blockade for the other antipsychotics indicates that the D2 site is important in this respect; it may be that therapeutic levels of these other drugs are governed more by the threshold for the appearance of (D2-mediated) extrapyramidal symptoms than by antipsychotic efficacy. One further confounding factor is that the increased affinity of clozapine for the D4 receptor is not consistently reported; Mills et al., (1993) found a Kd of 53 nM in their expression system, some fivefold higher than that reported by Van To1 et al., (1991). Olanzapine, the new clozapine-like drug presently in development, has an affinity at the D, site that is less than half its affinity at D2 (Ki of 27 and 11 nM, respectively; Moore et al., 1993); it remains to be seen whether this drug shares the clinical efficacy of clozapine. Seeman et al. (1993) attempted to determine D4 receptor density in human brain by indirect means; if their interpretation is correct, then striatal D, receptors may be increased in the striatum in schizophrenia. Other recent studies have complicated the issue still further; a polymorphism in the D, receptor gene in the human population has been identified (Van To1 et al., 1992). This polymorphism does not, however, appear to relate to differences in clozapine response (Shaikh et al., 1993). Nevertheless, while we have yet to see whether the D, protein is functionally important in the human brain, the development of D,-specific antagonists certainly provides potential for the treatment of schizophrenia. D, receptor polymorphisms reflect differences in the number and form of a repeat sequence in the gene, and hence the protein, structure (Van To1 et al., 1992). Modern molecular biological techniques have also demonstrated subtypes of the D2 receptor based on peptide length. D2 is found in a long (D2A)and a short (D2B) isoform, and a recent report finds that these two isoforms demonstrate a difference in their affinity for clozapine (Malmberg et al., 1993). It is notable that the D2B isoform, with a higher affinity for clozapine, is expressed in regions associated with a somewhat lower innervation by dopaminergic neurons. Whether this might impart some regional pharmacological selectivity has yet to be seen; however, it is notable in the light of the recent observation that clozapine has a higher affinity at D2-like receptors in the human frontal cortex in comparison to its action at striatal D2 sites (Mason and Reynolds, 1994).

VIII. Muscarinic Receptors A few antipsychotics have a relatively high affinity for the muscarinic acetylcholine receptor in brain tissue; for clozapine and thioridazine this is reportedly higher than their D2 receptor affinity (Richelson and Nelson, 1984).Muscarinic antagonism relates to the low incidence of extrapyramidal symptoms found with these drugs (Miller and Hiley, 1974); iatrogenic parkinsonism and dystonia are commonly treated with anticholinergic agents

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(McEvoy, 1983). Muscarinic blockade can lead to dry mouth and constipation. Conversely, however, excessive salivation has been reported following treatment with classical antipsychotic drugs (cited in Marsden et al., 1986); this side effect is a major problem in patients receiving clozapine (Fitton and Heel, 1990). Antagonism at muscarinic sites may be responsible for clozapine’s ability to prevent the inhibition of nigrostriatal cell firing that can be induced by classical antipsychotics. As mentioned in Section IV, this differential effect on mesolimbic and nigrostriatal dopaminergic systems is proposed to relate to “atypicality” of antipsychotics. On the other hand, anticholinergics may be psychotogenic, probably because of the reciprocity of dopaminergic and cholinergic systems in the brain. Tandon and Kane (1993) have suggested that the hypersalivation induced by clozapine reflects a partial agonist effect at muscarinic sites, an effect that may contribute to the antipsychotic efficacy of the drugs. However, studies from this laboratory have failed to find any direct evidence for an agonist effect of clozapine at M1, M2, or M 3 muscarinic receptor subtypes (G. P. Reynolds et al., unpublished). It seems unlikely that a partial agonist or other activity at the muscarinic receptor makes a substantial contribution to the efficacy of antipsychotics other than their ability to diminish extrapyramidal symptoms.

IX. 5-Hydroxytryptamine and Schizophrenia Since the identification of 5-hydroxytryptamine (serotonin, 5-HT) as a neurotransmitter in the early 1950s, there has been an interest in its possible importance in schizophrenia. The initial finding that the hallucinogenic drug LSD was an effective 5-HT antagonist led to the development of hypotheses based on deficiency of 5-HT or transmethylation of endogenous amines to form natural psychotogens. These hypotheses fell out of favor with the emergence of the dopamine hypothesis. Nevertheless, an intermittent interest in 5-HT systems in schizophrenia and its drug treatment has remained, fueled recently by the observations that some antipsychotics have antagonist action at 5-HT receptors and that other 5-HT receptor antagonists are effective in certain animal models of antipsychotic action.

A. 5-HT2 Receptor Antagonists 5-HT2 receptors are found in many brain regions and mediate a variety of behaviors, including some of those induced by high doses of amphetamine. Some of these behaviors have, in the past, been equated to psychosis (Sloviter et al., 1980), although there is no evidence for classical antipsychotic effects being mediated by 5-HT2 receptor blockade. Certainly no correlation exists between clinical potency and affinity for these receptor sites (Table IV).

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TABLE IV Affinities of Some Classical and Novel Antipsychotics for D, and 5-HT2 Receptors Ki values (nM)

Fluphenazine Thioridazine Chlorpromazine Clozapine Risperidone Olanzapine ICI 204636 Sertindole

5-HT2

D2

4.0 26 2.0 3.7 0.12 3.8 42b 0.38

1.0 21 18 105 3.0 11.0 260’ 0.46

D2I5-HTZa 0.25 0.8 9.0 28 25 2.9 6.2 1.2

Reference Reynolds (unpublished) Reynolds (unpublished) Reynolds (unpublished) Reynolds (unpublished) Leysen et al. (1992) Moore et al. (1994) Saller and Salama (1993) Hyttel et al. (1992)

G. G. G. G.

P. P. P. P.

The DJ5-HT2 ratio provides a measure of the relative in vitro selectivity of each drug for the SHT2 receptor. Approximate K, values estimated from reported 1C50 values.

’

Along with several other antipsychotics, clozapine is an effective 5-HT2 antagonist, with a higher affinity for these sites than for the D2 receptors. Its administration leads to a rapid down-regulation of 5-HT2 sites (Reynolds et al., 1983); an effect shared with many antidepressant drugs. Whether this effect is a consequence of 5-HT2 antagonism is unproven; nevertheless there is a substantial interest in the potential of mixed 5-HT2I D2 receptor antagonists in the treatment of schizophrenia. This approach has been given substantial support by the theoretical analysis of Meltzer and colleagues (1989) who demonstrated that “atypicalityyyin a range of antipsychotic drugs corresponds to high ratios of 5-HT2 and D2 receptor affinities. There are some problems with this study; Meltzer et al. (1989) compared the ratios of drug pKi values instead of their differences, which would be more mathematically correct. Nor do they include the substituted benzamides, such as sulpiride and remoxipride; these are considered atypical in that they have a low propensity to induce extrapyramidal symptoms and yet have essentially no effect at 5-HT2 receptors. Nevertheless, this work has served to stimulate the study of 5-HT2 antagonist action in the treatment of schizophrenia, and there are now several mixed 5-HT21D2receptor antagonists recently introduced or in development, including risperidone, olanzapine, sertindole, ICI 204636 (seroquel), amperozide, and MDL 100907, each of which has a higher affinity for 5-HT2 than D2 receptors. It has been shown that concurrent administration of 5-HT2 antagonists with classical antipsychotics can reduce extrapyramidal symptoms (Gelders, 1989), and early animal experiments by Costall et al. (1975) have shown that antagonists of 5-HT reduce catalepsy induced by antipsychotic drugs. The mechanism for this effect may relate to an influence of 5-HT2 receptors

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in dopamine systems. The 5-HT2 antagonist ritanserin activates dopamine neurons (Ugedo etal., 1989), and such antagonists also potentiate the stimulation of dopamine metabolism induced by D, receptor blockade (Saller et al., 1990). However this is only an acute effect; other experimental studies have failed to identify its basis in terms of the chronic modulation of dopaminergic activity by 5-HT2 blockade (Lappalainen et al., 1990). Nevertheless, electrophysiological (Sorensen et al., 1991) and biochemical (Schmidt et al., 1992) studies have shown that 5-HT2 antagonists reverse the effects of amphetamines on dopaminergic neurons, and chronic studies indicate that the 5-HT2 antagonist MDL 100907 has a clozapine-like selectivity in reducing the activity of A10, but not A9, neurons (Sorensen and Humphreys, 1993). This has been used to suggest the potential of pure 5-HT2 antagonists as antipsychotic agents. Casey (1993) investigated the effects in nonhuman primates of a range of mixed DZI5-HT2antagonists including risperidone and clozapine. He observed that all drugs, with the sole exception of clozapine, induced an acute dystonia that was independent of the 5-HT2 affinity, concluding that 5-HT2 antagonism in primates does not contribute to diminished extrapyramidal symptoms. Clinical studies with mixed 5-HT2ID2 antagonists are similarly far from being clear-cut. An early study of the efficacy of ICI 204636 in the treatment of schizophrenia indicated that it may be associated with a lower, although not absent, incidence of extrapyramidal side effects (Fabre, 1993).However, treatment with sertindole identified 26% of patients who required anticholinergic medication (McEvoy et a!., 1993). A low incidence of extrapyramidal symptoms or a low requirement for anticholinergic treatment has been reported by several groups for risperidone (e.g., Bersani et al., 1990). As mentioned earlier, one observation that may contribute to clozapine’s efficacy is its relatively low occupancy of D, receptors in vivo. This is unlikely to be shared by risperidone; PET investigation following a single 1-mg dose showed a D, receptor occupancy of about 50% (Nyberg et al., 1993), suggesting that therapeutic doses of 4-8 mg daily could well lead to around 80% receptor blockade. Thus the 5-HT2 blockade (of about 60% in vivo following 1 mg) induced by risperidone (Nyberg et al., 1993) does not appear to potentiate the antipsychotic effect of the D, receptor blockade, although it may diminish extrapyramidal symptoms associated with high D, occupancy. It is surprising that these results are not very consistent with the ex vivo receptor occupancy observed in rat brain in which a 300-fold preference for 5-HT2 over D, sites was reported (Schotte et al., 1989). A beneficial effect on negative symptoms is another action considered to be mediated by combined 5-HT2/D2 blockade. Risperidone can impove both positive and negative symptoms in schizophrenia (Bersani et al., 1990). This could relate to 5-HT2 receptor blockade; certainly the 5-HT2 antagonist ritanserin has been reported to improve both affective and negative symptoms in schizophrenia (Gelders, 1989). However, 5-HT2 antagonism

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is not a requirement for the improvement of negative symptoms during antipsychotic therapy; both sulpiride (Soni et al., 1990) and remoxipride (Laux et al., 1990) bring about some improvement in this respect. One further argument against a major role for 5-HT2 blockade in these indicators of “atypicality” is found in the action of chlorpromazine. This classical antipsychotic drug is also an effective 5-HT2 antagonist and, like clozapine, down-regulates these receptors (Matsubara and Meltzer, 1989) and yet is considered inferior to many newer antipsychotics. It may be, of course, that the in vitro assessment of drug-receptor affinities does not reflect relative receptor occupancies in vivo, although Matsubara et al. (1993)found that in vivo and in vitro binding was comparable for most antipsychotic drugs. Further PET studies are needed to determine whether chlorprornazine is an effective antagonist of human 5-HT2 receptors at clinical doses. B. 5-HT3 Receptors Another site of action of 5-HTthat has recently attracted interest in the development of potential antipsychotics is the 5-HT3 receptor (Tricklebank, 1989). 5-HT3 receptors do not occur in high densities in the brain other than in parts of the brain stem associated with the emetic response, although more are found in the hippocampus and amygdala than most other brain regions (Kilpatrick et al., 1987). Clozapine, but few other antipsychotics, binds to this site with affinity similar to its D, effect (Wading et al., 1990). Ondansetron, the first selective 5-HT3 antagonist available in the clinic, has been proposed to be of potential value for many psychiatric problems, including anxiety, addiction, memory disorders, and schizophenia. These proposals derive from a substantial body of basic pharmacological research primarily carried out by Costall and co-workers (1987). Thus, for example, ondansetron reportedly has inhibitory effects on limbic dopaminergic hyperfunction, an attractive indication of potential antipsychotic efficacy (Costall et a/., 1987). However, others have been unable to reproduce ondansetron’s effects on dopamine-mediated hyperactivity (Greenshaw, 1993). Similarly, clinical data have fairly consistently failed to meet the original high expectations of this drug. A large multicenter trial of ondansetron in schizophrenia was unable to provide convincing evidence of its value as an antipsychotic, although there is an anecdotal report to the contrary in a patient who did not respond adequately to classical antipsychotic treatment (White et a/., 1991b). Similar negative findings have been observed in a clinical study of the antipsychotic potency of zacopride, another 5-HT3 antagonist (Newcomer et al., 1992). C. 5-HTIA Receptors

The interest in 5-HT1A receptors in psychiatry lies mainly with the development of (partial) agonists at this site as anxiolytic agents and possibly

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antidepressants. However, clozapine, alone among antipsychotic drugs, appears to have an affinity for these receptors that is consistent with at least partial binding at normal drug dosages (Mason and Reynolds, 1992). It is also notable that buspirone, a partial agonist at the 5-HT1A receptor, exacerbates schizophrenic psychosis (Pantelis and Barnes, 1993), although other studies reviewed by these authors have not necessarily shown a consistent detremental effect of buspirone on psychosis. Interpretation of these studies is confounded by the fact that buspirone has effects on other transmitter systems, including dopamine. Recent evidence has emerged showing human cortical pyramidal neurons to be enriched with 5-HT1A receptors (Bowen et al., 1992). This provides a potential receptor mechanism for the modulation of cortical glutamatergic neurons, raising the possibility that an interaction with 5-HT1A receptors may contribute to the mechanism whereby clozapine exerts its unique action. Certainly such a mechanism might be consistent with the increasing evidence for glutamatergic dysfunction in schizophenia (see Section XIV).

X. Noradrenergic Systems Originally proposed 20 years ago, the suggestion that an abnormality of noradrenaline transmission underlies schizophrenia was based on the fact that noradrenergic systems were thought to be involved in central reward pathways (Stein and Wise, 1971). Thus a noradrenergic deficit could lead to a loss of drive and anhedonia, which is a model appropriate for the syndrome of primarily negative symptoms. This involvement of noradrenaline is no longer considered accurate, and the evidence for a primary role for a noradrenergic dysfunction in schizophrenia is also unconvincing (Iversen et al., 1983). However, there is circumstantial evidence supporting an involvement of noradrenaline in schizophrenic symptomatology (van Kammen et al., 1990). Noradrenaline does, however, interact with dopaminergic systems in various regions of the brain. Tassin (1992) has reviewed the evidence for this interaction in the cortex and pointed out that a reciprocal control exists between dopaminergic D,receptors and adrenoceptors. Many antipsychotic drugs are antagonists at adrenoceptors, although the a1blockade shared by several of these drugs (Richelson and Nelson, 1984) is considered to be responsible for some of the unpleasant side effects, including postural hypotension and effects on sexual function. However, Tassin (1992) concludes that a1blockade, by disinhibiting dopaminergic transmission via D1receptors, may play a role in the antipsychotic response, particularly in diminishing positive symptoms. Direct clinical evidence in support of such an almediated antipsychotic action is, however, lacking. Initial interest in high doses of the p receptor antagonist propranolol having antipsychotic effects (Yorkston et al., 1977) has not remained; the

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positive results that were originally obtained may have been related to a pharmacodynamic interaction between propranolol and antipsychotics (Pugh et al., 1983). Nevertheless, such /3 blockers do have a role in the symptomatic relief of the extrapyramidal side effect of akathisia. Clozapine, alone among antipsychotics, has an effective a, antagonism (Richelson and Nelson, 1984), which is probably responsible for its ability to increase plasma noradrenaline. There is little direct evidence that this a2effect might also contribute to clozapine’s efficacy. However, a recent study has shown that supplementation of treatment by a classical antipsychotic drug, fluphenazine, with the a, antagonist idazoxan leads to a further improvement of both positive and negative schizophrenic symptoms (Litman et al., 1993). The improvement was similar to the response induced by clozapine in these patients, implying that a, antagonism may well contribute to the clinical efficacy of the latter drug. Litman et al. (1993) suggest that this effect may relate to an enhancement of noradrenergic transmission resulting from blockade of presynaptic a, autoreceptors. However, an alternative hypothesis might be that the effect is on the postsynaptic a, sites, which have a tonic inhibitory effect on cortical neurons. Blockade of these sites may lead to a potentiation of certain glutamatergic systems; this action is consistent with evidence suggestive of glutamatergic deficits in schizophrenia (see Section XIV). Further studies of a2 antagonists as adjuncts to D, receptor antagonists would be valuable in the identification of potential drugs for the treatment of refractory patients with schizophrenia.

XI. u Receptors One receptor that has attracted interest recently as of possible importance in antipsychotic action is the haloperidol-sensitive u recognition site. The role of this site in brain function, originally confused with the “PCP binding site” on the NMDA receptor complex, is unclear. Haloperidol has a high affinity for the site, which may mediate the psychotogenic activity of certain benzomorphans (Chavkin, 1990). Some of the clinically effective phenothiazine neuroleptics also have an affinity for the u site in the submicromolar range. In addition, many of the recently developed antipsychotics (but not, however, clozapine) have significant potency at the haloperidolsensitive u site (Largent et al., 1988). Thus remoxipride, with a lower incidence than haloperidol of several unwanted side effects, has a relatively selective action at the u and D2receptors (Kohler et al., 1990). However, several u ligands have not been effective in the clinical treatment of schizophrenia, making it unlikely that action at v sites can make an important contribution to antipsychotic efficacy. Although there have been reports of changes in the density of the a sites in brain tissue in schizophrenia (Weissmann et al., 1991), these may be due to an effect of prior treatment with haloperidol, which down-regulates a site density (Reynolds et al., 1991).

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It is notable that the red nucleus has a high density of u recognition sites and that this area is implicated in the generation of dystonia; u site ligands injected into the red nucleus can produce dystonic motor dysfunction in animals (Matsumoto et al., 1989).However, treatment with remoxipride, which demonstrates a higher affinity for u sites than for dopamine D2 receptors, does not induce more than fairly low levels of dyskinesia (e.g., Laux et al., 1990). Nevertheless, an understanding of the relative involvement of different subtypes of the u recognition site, as well as a means of distinguishing agonist from antagonist effects at this site, is needed before the importance of u receptors in the action of antipsychotic drugs can be fully assessed.

XII. Benzodiazepines and y-Aminobutyric Acid y-Aminobutyric acid (GABA) has long been implicated in the neurochemical pathology of schizophrenia. A “GABA hypothesis” first emerged from observations of the reciprocal nature of the actions of GABA and dopamine in the basal ganglia (Roberts, 1972). Although studies of brain tissue taken at postmortem have provided little evidence for a dysfunction of GABA in these brain regions, recent work has identified neurochemical changes relating to GABAergic neurotransmission in parts of the brain associated with neuropathological abnormalities in schizophrenia. Thus deficits of (presumably GABAergic) interneurons have been identified in the prefrontal and cingulate cortices (Benes et al., 1991), and increased densities of GABA-A receptor binding have been reported in the cingulate cortex in schizophrenia (Benes et al., 1992), an effect presumed to relate to a compensatory up-regulation of postsynaptic receptor sites. Regions of the medial temporal lobe, the part of the brain in schizophrenia in which neuronal deficits or disorder have been most frequently reported (Roberts, 1991), demonstrate diminished densities of ligand binding of [3H]nipecotic acid to GABA uptake sites (Reynolds et al., 1990), a marker for the integrity of GABAergic nerve terminals. As mentioned in Section 11, the decreased densities that are found in the hippocampus of the left hemisphere correlate with the increase in amygdala dopamine also found in this side of the brain (Reynolds et al., 1990). Losses of cholecystokinin (discussed in Section X1II.B) and somatostatin in limbic brain tissue in some schizophrenic patients (Roberts et al., 1983) are consistent with losses of subgroups of GABAergic neurons, in which these neuropeptides are colocalized (Somogyi et al., 1984). A recent study in brain tissue in schizophrenia found an increase above control values in the binding of a single concentration of radiolabeled flunitrazepam to part of the hippocampus (Kiuchi et al., 1989), although it has not been confirmed that there was any up-regulatory increase in hippocampal benzodiazepine receptors (Reynolds and Stroud, 1993).

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Benzodiazepines act by potentiating the action of GABA at the GABAA receptor complex. They are widely used as anxiolytics and hypnotics and may be of value in the treatment of schizophrenia. Thus they have been reported to be effective alone in high dose (e.g., Beckmann and Haas, 1980) or as an adjunct to neuroleptic treatment (Wolkowitz eta!., 1988), although their antipsychotic efficacy alone in conventional doses is unconvincing (Lingjaerde, 1991). This may reflect the ubiquitous distribution of GABA systems, and of benzodiazepine/GABA-A receptors, in the brain. Drugs acting at these sites will inevitably have multiple actions on brain function without a specific action on limbic GABA systems. However, a new generation of benzodiazepine partial agonists is being developed at present; these demonstrate some selectivity between receptor subtypes and brain regions. One of these drugs has antipsychotic effects in some preliminary studies (Delini-Stula et al., 1992), although it has yet to be determined whether this effect might relate directly to an amelioration of the hippocampal GABAergic deficit.

XIII. Neuropeptide Systems The rapid development of interest in the neurochemical anatomy and behavioral neurophysiology of the neuropeptides has provided some interesting hypotheses for their potential in antipsychotic pharmacology. Many members of the growing band of neuroactive peptides have been implicated in schizophrenia, albeit often with minimal supporting evidence. Three groups of neuropeptides have been studied at great depth for their potential in the development of novel, and specific, treatments for schizophrenia: neurotensin, cholecystokinin (CCK), and the opioid peptides, all three of which are closely involved with dopaminergic systems in the human brain.

A. Neurotensin Neurotensin is a tridecapeptide that is found in several dopaminergic terminal regions, notably including mesolimbic structures, which partly reflects its coexistence with dopamine in some mesolimbic or mesocortical neurons (Seroogy et al., 1988). While abnormalities of brain or CSF concentrations of neurotensin have been reported in schizophrenia, these are not consistently found. Interestingly, however, the peptide is increased following chronic antipsychotic drug treatment, and these studies demonstrate a potentially important dichotomy: while haloperidol induces neurotensin increases in both caudate and accumbens nuclei, clozapine only affects the nucleus accumbens (Davis and Nemeroff, 1988). These results, along with other evidence for mutual regulatory effects between dopamine and neurotensin, have led to consideration of the peptide as having antipsychotic properties,

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an approach pursued with some success by Nemeroff and colleagues. Such a possibility is supported by its effects on various animal models, including that of conditioned avoidance responding (Luttinger et al., 1982). However, whether a neurotensin analog or agonist able to penetrate the brain will prove to be successful in the clinical treatment of schizophrenia has yet to be seen.

B. Cholecystokinin CCK is another neuropeptide found in some mesolimbic dopamine neurons (Hokfelt etal., 1980), although the great majority of CCK immunoreactive neurons also contain neurotransmitter GABA. CCK has been reported to be diminished in certain limbic brain structures in schizophrenia (Roberts et al., 1983); this has been interpreted as reflecting losses of GABAergic neurons (Reynolds, 1989). Nevertheless, the involvement of CCK with dopaminergic systems has stimulated interest in the possible role of the peptide in antipsychotic action. It has been suggested that CCK and the CCK agonist ceruletide are able to inhibit limbic dopaminergic activity, with behavioral effects following intracerebral injection in rats that resemble those of antipsychotic drugs (Van Ree et al., 1983). While there have been some positive effects reported in open trials of CCK or ceruletide in schizophrenia, adequately controlled trials have been few and disappointing (Verhoeven et al., 1988), and it is too soon to suggest that CCK agonists have a valuable role in the treatment of schizophrenia (Montgomery and Green, 1988). C. Opioid Peptides

Bissette et al. (1986) have pointed out that the original interpretations of the behavioral effects of @endorphin as either catatonia or neurolepticlike catalepsy led to two mutually exclusive hypotheses for the potential

involvement of opioid peptides in psychosis: that they were psychotogenic or that they were antipsychotic. In retrospect we can see that neither hypothesis is soundly based. Each approach has had its proponents, although interest has certainly waned over the past decade. The opioid psychotogenicity hypothesis has been tested by administration of antagonists such as naloxone; this drug, however, has not been consistently shown to be antipsychotic and, when reported to be of value in certain patients, its effect is usually fairly transient. It is likely that the akinetic effect of P-endorphin relates to the role of opioid peptides in the motor functions of the basal ganglia. The concentrations of striatal Met-enkephalin are increased by chronic antipsychotic drug treatment (Hong et al., 1978), providing some support for opioid peptides having a role as endogenous antipsychotics. Intraventricular administration

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of p-endorphin can diminish conditioned avoidance responding (Luttinger eta!., 1982), which is also indicative of a (dopamine-mediated) antipsychotic potential. But clinical trials have proven disappointing, although it is hardly surprising that short-term injections of peptides such as P-endorphin that are unlikely to reach the brain in any substanial quantity fail to provide positive results. The “opioid” peptide that has been studied the most as an antipsychotic agent is des-tyr-y-endorphin (DTE). De Wied and his colleagues have long pursued this approach, which is based on the behavioral effects of this endorphin fragment in animal models predictive of antipsychotic efficacy. DTE has no opiate-like activity but is proposed to act at sites that allow endogenous endorphins to modulate mesolimbic dopamine systems (Van Ree and De Wied, 1982). However, Luttinger et al., (1982) failed to observe any effect of DTE on conditioned avoidance responding. Clinically, the promise shown in open studies failed to be confirmed by controlled investigations (reviewed by Verhoeven et al., 1988), although these authors remain convinced of the potential of DTE for the treatment of a subgroup of schizophrenic patients. Although neuropeptides have not fulfilled their initial promise in understanding schizophrenia and its treatment, they do provide means of influencing dopamine or other transmitter systems with a regional specificity. Thus it is still conceivable that, with the future development of centrally acting peptidergic agonists or antagonists, novel antipsychotic compounds may emerge.

XIV. Glutamate Systems The recent increasing interest in glutamate systems as “a new target in schizophrenia” (Wachtel and Turski, 1990) stems from three observations. One is the psychotomimetic effect of phencyclidine (PCP), a drug of abuse that is considered to produce a better human (and presumably animal) model of schizophrenia than amphetamine, since PCP induces negative symptoms in addition to an acute psychosis of primarily positive symptoms. These behavioral effects of PCP are due, at least in part, to its ability to block the ion channel associated with the glutamatergic N-methybaspartate (NMDA) receptor complex (Javitt and Zukin, 1991). PCP and other noncompetitive NMDA receptor antagonists such as dizolcipine (MK801) bind to the open conformation of the NMDA receptor and act as negative allosteric modulators to close the cation channel and thereby noncompetitively antagonize the effect of glutamate. Drugs that bind to the PCP receptor therefore inhibit the functioning of normal NMDA receptor-mediated glutamatergic neurotransmission. Second, if antagonist action at this site is psychotogenic, it is conceivable that schizophrenia might relate to a dysfunction

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of glutamategic transmission. There is evidence for this from postmortem neurochemical studies, particularly in the frontal cortex, where increased density of pre- and postsynaptic markers of glutamatergic neurons has been reported (Deakin et al., 1989), although we have been unable to confirm these increases, finding only deficits of glutamate uptake sites in the caudate and accumbens nuclei, structures receiving glutamatergic projections from cortical regions (Reynolds and Cutts, 1994). The third source of evidence is the close interrelationship between glutamate and dopamine systems; Carlsson and others have constructed elegant proposals for a dysfunction of this relationship in schizophrenia (Carlsson and Carlsson, 1990; Kim et al., 1980). Although necessary for an understanding of the antipsychotic action of dopamine antagonists in the context of a glutamatergic neuropathology of schizophrenia, such proposals d o not explain the (primarily negative) symptoms that are less responsive to such treatment. The main site at which glutamatergic abnormalities are reported is the frontal cortex, and dysfunction of this region, indicated by structural and functional imaging studies, has been associated with negative symptomatology in schizophrenia. Present neurochemical evidence supports hypotheses of either increased or decreased glutamatergic function in schizophrenia, although the PCP model is more consistent with the latter. No antipsychotic presently in use has direct effects on glutamatergic transmission at normal clinical dosages. Nevertheless, glutamate receptors, and particularly the NMDA subtype, offer a novel approach to the development of potential treatments for schizophrenia. These receptors have facilitatory effects on dopaminergic transmission in subcortical regions since they can stimulate dopamine release. In the frontal cortex the action of glutamate on dopamine systems is less clear; some in vivo studies suggest that NMDA receptors diminish dopamine utilization (Hata et al., 1990), although in vitro release of dopamine from the frontal cortex is stimulated by both NMDA and non-NMDA glutamate receptors (Jones et al., 1993). Possible differences between cortical and subcortical glutamatergic control of dopamine systems present an interesting dichotomy that parallels some proposals relating to the dopamine hypothesis of schizophrenia; while it is generally accepted that dopaminergic hyperactivity relates particularly well to positive symptoms, it has been suggested that dopamine hypofunction may underlie negative symptomatology, in which frontal cortical dysfunction has been implicated. However, no neurochemical evidence from postmortem studies has offered any direct support of this hypothesis (Reynolds, 1989). Consistent with the psychotogenic effects of noncompetitive NMDA receptor antagonists such as PCP and dizocilpine, a decrease in prepulse inhibition (see Section 1II.D) is observed after administration of these compounds but not after competitive NMDA receptor antagonists binding to the glutamate site (Mansbach, 1991). This behavioral effect is not influenced by dopaminergic D2 antagonists since it is not reversible by haloperidol

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(Geyer et al., 1990). These results serve to strengthen the theory that manipulation of the NMDA receptor complex might be a valid target for antipsychotic drug development, particularly in treatment-resistant patients. The NMDA receptor complex has several sites open to pharmacological influence in addition to the transmitter-binding site and the ion channel. For example, glutamate action at this site has an essential requirement for glycine; thus glycine has a positive modulatory effect on the glutamate/ NMDA receptor. Glycine itself and the glycine prodrug milacemide have been investigated as potential antipsychotics. A blind, placebo-controlled trial of high-dose glycine in schizophrenics also receiving classical antipsychotics improved negative symptoms (Zukin et al., 1993),while milacemide, despite crossing into the brain more easily than glycine, has no antipsychotic efficacy (see Gerlach, 1991). Noncompetitive antagonism of the glutamate/NMDA receptor may be brought about by antagonist action at the glycine-binding site. One compound with this effect is HA966; it can inhibit the behavioral and biochemical effects of amphetamine and PCP in activating the mesolimbic dopamine system, without affecting dopamine function in nonstimulated animals (Hutson et al., 1991). Although this is a long way from a clinical antipsychotic response, it does provide an exciting stimulus to the development of novel antagonists at the glycine/NMDA receptor as potential drugs for the treatment of schizophrenia.

XV. Concluding Remarks This review attempted to cover the major approaches to drug development for the treatment of schizophrenia. In doing so, we tried to describe the pharmacological rationale for these approaches and, where possible, relate this to our still very limited understanding of the neuronal basis of the disease. Inevitably the decision on what is included is an arbitrary one. Thus we have not been totally comprehensive; some of the adjuvant treatments occasionally employed-such as the anticonvulsant drugs (Van Valkenburg et a/., 1992)-have not been discussed nor have we mentioned various other drugs that have yet to be proven effective for clinical use. It is clear that in many cases the development of antipsychotic drugs still relies on heuristic observation, with the essential mechanisms of action remaining obscure. Nevertheless, it is hoped that we have indicated that pharmacological research is coming closer to defining those mechanisms. Moreover, as genetic and epidemiological studies tell us more about the etiology of schizophrenia, and as neuropathology and neurochemistry better define the neuronal systems affected, we should be able to develop more rational approaches to the drug treatment of this complex disorder.

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