Schizophrenia Research, Elsevier

SCHIZO

4 (1991) 121-156

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0013 1

Mechanisms of action of atypical antipsychotic drugs Implications Ariel

Y. Deutch,

Bita

for novel therapeutic Moghaddam, Benjamin

strategies

for schizophrenia

Robert B. Innis, John H. Krystal, S. Bunney and Dennis S. Charney

George

K. Aghajanian,

Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT 06510. U.S.A. and Department of Veterans Affairs Medical Center, West Haven, CT 06516, U.S.A. (Received

11 April

1990, accepted

27 April

1990)

The mechanisms which contribute to the actions of atypical antipsychotic drugs, such as clozapine and the putative atypical agents remoxipride and raclopride, are reviewed. Examination of available preclinical and clinical data leads to two hypotheses concerning the mode of action of atypical antipsychotic drugs. The first hypothesis is that antagonism of the dopamine D, receptor is both necessary and sufficient for the atypical profile, but that interaction with subtypes of the D, receptor differentiates typical from atypical antipsychotic drugs. The second hypothesis has been previously advanced, and suggests that a relatively high ratio of serotonin 5-HT,: dopamine D, receptor antagonism may subserve the atypical profile. It seems likely that the atypical antipsychotic drug profile may be achieved in more than one way. Key words: Atypical receptor;

antipsychotic drug; (Schizophrenia)

Dopamine;

Serotonin;

INTRODUCTION

Since the advent of pharmacotherapy for schizophrenia there has been a search for new and better antipsychotic agents. Recently this search has focused on attempts to improve therapeutic efficacy and reduce side effects. The synthesis of new psychoactive compounds which are useful in the treatment of psychiatric disorders, including schizophrenia, has generally been based on structural similarities to drugs of proven efficacy, although often serendipity has been of equal importance. For example, clozapine, a dibenzodiazepine, was synthesized in the early 1960s (see Hippius, 1989). The synthesis of this compound was based upon a structural similarity to the tricyclic antidepres-

Correspondence IO: A.Y. Deutch, Psychiatry Service/l 16A, Veterans Administration Medical Center, Cambell Avenue, West Haven, CT 06516, U.S.A.

0920-9964/91/$03.50

0

1991 Elsevier Science Publishers

Clozapine;

Raclopride;

D, dopamine

receptor;

5-HT,

serotonin

sants, but led unexpectedly to the discovery of a new class of antipsychotic drugs useful in the treatment of schizophrenia. Animal tests used to establish the preclinical profile of clozapine suggested antipsychotic efficacy with a low incidence of extrapyramidal side effects (EPS), and clinical trials were instituted (for reviews, see Schmutz and Eichenberger, 1982; Hippius, 1989). Open clinical trials of clozapine for the treatment of schizophrenia included one study which indicated that clozapine was antipsychotic but produced no EPS (Gross and Langner, 1966). This conclusion was verified by more extensive controlled studies conducted in Europe (Berzewski et al., 1969; Angst et al., 1971a), and the position of clozapine as an antipsychotic drug which did not produce EPS was consolidated by a double-blind study in 1971 (Angst et al., 1971b). Clozapine was subsequently used widely in Europe for the treatment of schizophrenia. How ever, a report documented a high incidence of clozapine-induced agranulocytosis in Finland

B.V. (Biomedical

Division)

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(De la Chapelle et al., 1977). Other reports soon followed which established that treatment with clozapine resulted in a l-2% incidence of agranulocytosis. As a result, the use and availability of clozapine were considerably reduced. However, therapeutic interest in clozapine continued, primarily because of the positive findings of several double-blind studies comparing clozapine to chlorpromazine or haloperidol: clozapine was consistently reported to be a superior antipsychotic for treatment-resistant schizophrenic patients (Fisher-Cornellson and Ferner, 1976; Shopsin et al., 1979; Claghorn et al., 1987). These findings were replicated by the Clozaril Collaborative Study Group (Kane et al., 1988, 1989) in an elegant prospective design study in which treatment-resistant schizophrenic patients were identified. This investigation reported that clozapine substantially alleviated psychosis in 30% of treatment-resistant patients, whereas only 4% were benefited from chlorpromazine. The long-term effects of clozapine have also been reported to be superior to those observed with standard antipsychotic drugs (Povlsen et al., 1985; Kuha and Miettineo, 1986; Lindstrom, 1987). Clozapine has recently been approved for use in treatment-resistant schizophrenic patients in the United States; the approval was made on the unprecedented condition of the establishment of a patient monitoring system which includes weekly blood counts to detect reduced white blood cell counts. Atypical antipsychotic drugs, including clozapine, differ from typical antipsychotic drugs (neuroleptics) in that they have a markedly lower or absent propensity for the induction of extrapyramidal (parkinsonian) side effects (EPS) (see Casey, 1989). Atypical antipsychotic drugs also differ from typical antipsychotic agents in that they do not elevate prolactin levels. For the purpose of the present paper, we will define atypical antipsychotic drugs as those antipsychotics which are clinically effective and which do not have as side effects overt parkinsonian symptoms. We do not include among the EPS akathesia, since it appears that akathisia is subserved by different neurochemical mechanisms (as reflected by the therapeutic efficacy of /3adrenoceptor antagonists (Lipinski et al., 1983; Angrist et al., 1989) and the fact that akathisia is not typically observed in patients with Parkinson’s disease). It is also important to note that although

clozapine clearly is effective in treatment-resistant schizophrenic patients, and targets negative as well as positive symptoms, our definition of an atypical antipsychotic drug does not include the criterion that the drug possesses therapeutic superiority when compared to neuroleptics (typical antipsychotic drugs), but simply that the atypical antipsychotic drug be therapeutically effective. We have defined an atypical antipsychotic in this manner because few of the putative atypical antipsychotic drugs have been evaluated in treatment-resistant schizophrenic patients. We have also not included prolactin response as a defining characteristic, since the side effects associated with elevated prolactin (e.g., gynecomastia) are rarely bothersome enough to severely compromise patient compliance with pharmacotherapy. Finally, we do not include as a criterion for atypical antipsychotic drugs amelioration of negative symptoms, although this effect is desirable; at least one study has reported that clozapine and haloperidol are equally effective on negative symptoms in acute and chronic schizophrenic patients (Angst et al., 1989). Thus, the definition used in this paper focuses on the important aspect of atypical antipsychotic drug action, namely that the drugs be therapeutically effective in the treatment of schizophrenia without producing EPS, since the motor side effects result in patient distress and reduced compliance with the medication regimen. It should also be noted that there may be more than one type of atypical antipsychotic drug profile. In our definition of atypical antipsychotic drug we target clinical efficacy and reduced EPS. Yet it is apparent that clozapine is of therapeutic benefit in patients who do not respond to typical antipsychotic drugs, such as haloperidol (Kane et al. (Clozaril Comparative Study Group), 1988, 1989), i.e., that clozapine is superior to haloperidol in this group of patients. Other drugs which are thought to be atypical antipsychotic drugs have not yet been rigorously tested in comparison trials. Thus, it is possible that there are (1) atypical antipsychotic drugs which lack the propensity for induction of EPS anA are therapeutically superior to typical antipsychotic drugs, and (2) atypical antipsychotic drugs which are equi-efficacious to typical antipsychotic drugs but do not induce EPS. Among the most important aspects of clozapine is the potential insight which it may offer into the

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development of novel and more effective antipsychotic drugs, and insights concerning the pathophysiology of psychotic disorders. This paper will discuss some mechanisms which may contribute to the therapeutic efficacy of clozapine. The receptor binding profile, biochemical, and electrophysiological characteristics of antipsychotic drugs (including clozapine, other putative atypical antipsychotic drugs, and standard neuroleptics) will be reviewed. In addition, the findings of clinical efficacy studies using putative novel antipsychotics will be evaluated. We will attempt to synthesize the available data and define those attributes necessary for an antipsychotic drug to possess an atypical profile, and what key factors should be considered in the development of new antipsychotic drugs.

RECEPTOR BINDING PROFILE ANTIPSYCHOTIC DRUGS

OF

In vitro receptor binding prqjile Most studies which have attempted to define the mechanisms which subserve the therapeutic actions of antipsychotic drugs have focused on the receptors with which these drugs interact. The determination of the receptors at which antipsychotic drugs act has focused on the dopamine (DA) receptors, particularly the D, DA receptor, as a potential site through which the antipsychotic properties are mediated. The clear association between D, DA receptors and antipsychotic drugs has led to the dopamine hypothesis of schizophrenia; this viewpoint has in turn led to continued effort being devoted to the development of drugs which act at central DA receptors for the treatment of schizophrenia. More recently, the increased focus on the prototypic atypical antipsychotic drug, clozapine, has turned attention to central receptors other than the DA receptors, since in vitro binding data indicate that clozapine (compared to haloperidol and most typical antipsychotic drugs) has a lower affinity for the D2 DA receptor. The identification of sites of action of clozapine other than the D, receptor has also led to a reevaluation of the dopamine hypothesis of schizophrenia, and calls for the modification of the DA hypothesis. We will discuss in this section those receptor systems which both in vitro and in

vivo receptor binding methodologies have shown to be targeted by the antipsychotic drugs. Dopamine D, receptor. Central dopamine receptors have probably received the most intense scrutiny of all the transmitter receptors as a candidate site at which typical and atypical antipsychotic agents act. Carlsson and Lindquist (1963) were the first to report that haloperidol and chlorpromazine resulted in an increase in brain concentrations of the DA metabolite 3-methoxytyramine but did not alter levels of the parent amine; they hypothesized that neuroleptics block catecholamine receptors which results in a disruption of Subsequent catecholaminergic transmission. studies using approaches to directly label the dopamine receptor revealed that neuroleptics block the dopamine receptor (Clement-Cormier et al., 1974; Seeman et al., 197.5) and that clinical neuroleptic potency correlated well with the ability of antipsychotic drugs to block DA receptor binding (Creese et al., 1976; Seeman et al., 1976). In particular, the correlation between presumed clinical potency and binding of what has since been designated the D, DA receptor was quite high (Snyder et al., 1975; Kebabian and Came, 1979; Peroutka and Snyder, 1980). In contrast, there is a poor correlation between clinical efficacy and binding to a number of other receptors (muscarinic cholinergic, histamine HI, 5-HT,, and a,) (Peroutka and Snyder, 1980). The correlation between clinical efficacy and D, binding potency has led to the prevailing notion that all antipsychotic drugs have in common D, receptor antagonism. This concept has been a guiding force in strategies aimed at developing new antipsychotic drugs. In addition, reports of an increased number of striatal D, receptors in schizophrenic brain not attributable to neuroleptic treatment (Seeman, 1987; Seeman et al., 1987) have bolstered the idea that D, receptors are in some manner critically altered in schizophrenia. The concept that D, antagonism is critical for the antipsychotic actions of neuroleptics has thus received considerable support, and until recently all known clinically useful typical and atypical antipsychotic drugs were believed to be relatively potent antagonists at the D, site (Creese et al., 1976; Meltzer and Stahl, 1976; Seeman et al., 1976). Recently, four open clinical trials suggested that rimcazole, a sigma opiate antagonist which is

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essentially devoid of activity at D, (or D,, 5-HT,, pi, or muscarinic cholinergic sites; see below), possessed antipsychotic efficacy. However, more recent double-blind studies failed to reveal clinical efficacy, and clinical trials of rimcazole have ceased (see below). At the present time there are not (to the best of our knowledge) any exceptions to the rule that antipsychotic agents are (to some degree) D, antagonists. While it appears that all antipsychotics bind to the D, receptor site, clozapine and other putative atypical antipsychotic agents have a lower affinity in vitro for the D, site than do typical antipsychotic drugs (Meltzer et al., 1989). Nonetheless, there is some overlap between those agents which are considered to be atypical (at least on the basis of preclinical screening measures) and those thought to be typical. The inability to completely differentiate typical and atypical antipsychotics on the basis of D, binding has been interpreted to indicate that D, receptor antagonism is by itself insufficient to account for the atypical profile, and that some feature in combination with D, antagonism must subserve the mode of action of atypical antipsychotics (Meltzer et al., 1989) (see below, D,:5-HT, interactions). An alternative hypothesis is that D, antagonism is both necessary and sufficient for an atypical antipsychotic profile, but that action at different D, receptor subtypes determines which antipsychotic agents will exhibit an atypical profile. Consistent with this interpretation are recent open clinical trials of certain selective D, antagonists. The highly selective D, antagonist sulpiride (see Andersen, 1988) is clinically useful in the treatment of schizophrenia (Ishimaru et al., 197 1; Alfredsson et al., 1984; Gerlach et al., 1985). However, most clinical trials suggest that sulpiride is no less likely to induce EPS than haloperidol, thus indicating that a selective D, antagonist may act as an antipsychotic but with the motor side effects of typical neuroleptics (Alfredsson et al., 1984; Harnryd et al., 1984; Gerlach et al., 1985). In contrast, two open clinical trials of the selective and potent D, antagonist raclopride (Kohler et al., 1985; Andersen, 1988) suggest that it is an effective antipsychotic that produces little or no parkinsonian symptoms, although akathisia is observed in some patients (Cookson et al., 1989; Farde et al., 1989a,b); both studies also revealed a relatively

small and transient increase in prolactin levels. While one cannot rely upon open trials to determine the antipsychotic efficacy of a drug, open trials do engender limited confidence in the ability to identify those drugs which possess EPS. If there is validation of these preliminary data indicating that the selective D, antagonist raclopride is both clinically useful and has a low propensity for induction of EPS, the hypothesis that action at a critical D, receptor subtype is sufficient for an atypical profile will be strengthened. The classification of multiple D, receptors is made on the basis of the observation that multiple mRNAs encoding for D, receptors arise from alternative splicing of a D, gene sequence (Bunzow et al., 1988; Dal Toso et al., 1989; Giros et al., 1989; Selbie et al., 1989; Chio et al., 1990). These mRNAs differ by only 87 bases; the site of the additional 29 amino acids in the so-called D,, protein product is in the third cytoplasmic loop of the receptor, and is believed to be at or near the G protein recognition site. The limited analysis of the binding profiles of D,, and D,, receptors expressed in cell lines has revealed no significant differences between the two isoforms. However, these binding studies have not examinationed the ability of atypical antipsychotic drugs to bind to the two isoforms. Thus, it is not known to what degree preferential binding to these two D, isoforms may contribute to the differences between typical and atypical antipsychotic drugs. Ogren and associates (Ogren et al., 1986; Ogren and Hogberg, 1988) have previously suggested that the different actions of typical and atypical antipsychotic drugs on dopamine-mediated behavior may be attributable to interactions with subclasses of D, receptors. It should be noted that since the two D, isoforms differ only in the third cytoplasmic loop, thought to be distal to the ligand-binding domain, the two D, isoforms may not differ in their binding profile, but rather that differences may occur in transduction mechanisms (see De Keyser et al., 1989). However, a conformational change in the receptor attributable to the additional 29 amino acids may conceivably alter the ligand-binding domain. If differences between the D, subtypes only occur at or near the G protein coupling site, and do not alter in binding, differences between the two forms could then be determined by post-

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receptor transduction mechanisms. Such a hypothesis might explain why chronic administration of both typical and atypical antipsychotic drugs (which result in marked behavioral evidence suggestive of receptor supersensitivity) elicits only a small increase in striatal D, receptor density, and why repeated administration of clozapine has been reported to have no effect on the number of D, receptors (Seeger et al., 1982; Rupniak et al., 1984). The relative abundance of the two D, isoforms may differ across different brain regions (Giros et al., 1989; Meador-Woodruff et al., 1990) and thus the actions of typical and atypical antipsychotic drugs (which differ in their effects on DA metabolism in a regionally specific manner; see below) may be differentiated. This could occur in the face of no apparent differences in the binding domains of the receptor isoforms since G protein uncoupling can affect agonist binding. The interaction of different DA antagonists with regionally specific D, receptor isoforms may explain the differences between certain DA agonists and antagonists in actions on subsets of striatal DA axons (Fuxe et al., 1978). In addition to these differences in D, receptors, D, receptors are extensively modified (glycosylated) by post-translational processes. The posttranslational processing results in different molecular weight forms of the D, receptor which may be expressed in a regionally specific manner (Amlaiky and Caron, 1985, 1986). Some electrophysiological data are consistent with regionally-specific subtypes of D, DA receptors (Thierry et al., 1986; Sesack and Bunney, 1989). It is unclear if there are additional D, mRNAs encoding for additional D, receptors. D, receptors in pituitary tumors have been reported to differ from D, receptors in the striatum, both in terms of responsiveness to chronic neuroleptic treatment (Goldstein, 1990) and in terms of molecular weight analysis of subunits (Bouvier et al., 1990; Goldstein, 1990). Furthermore, preliminary data have suggested the existence of a third D, mRNA, designated DZy, also derived from alternative splicing of the D, gene identified by Bunzow et al. (I 988). Recent reports (Todd et al., 1988; O’Malley et al., 1989) have suggested an additional D, receptor which is not derived from alternative splicing of the D, gene of Bunzow et al. (1987). This receptor (which has atypical ligand binding

characteristics) has been reported to mediate an inward gated Ca * + channel (O’Malley et al., 1989). However, Wolf and Kapatos (1989) have indicated that stimulation of D, receptors decreases both basal [Ca2+li and depolarization-elicited increases in [Ca2+li in cells of the adenohypophysis (but not striatum). It is possible that additional D, receptor forms will be identified, particularly in light of the recent advances in the molecular biology of the D, gene. Identification of additional D, isoforms will be carefully scrutinized to determine if they have different binding characteristics, particularly in reference to the typical-atypical antipsychotic drug distinction. It should be emphasized that while we have discussed the possible involvement of different D, receptor isoforms in determining the atypical antipsychotic drug profile, these isoforms may not necessarily conform to the two known isoforms which we designate D,, and D,,. Other D, receptor proteins which do not arise from alternative splicing of the characterized D, gene may be uncovered, and these may be the hypothesized target(s) with which atypical antipsychotic drugs interact. Dopamine D, receptor. The D, DA receptor differs from the D, site in that under most conditions it is positively coupled to adenyl cyclase, whereas the D, receptor is either negatively coupled or not coupled to adenyl cyclase (see Seeman and Grigoriadis, 1987). There is a high correlation between D, and D, receptor binding by neuroleptics. Atypical antipsychotics as a group are less potent inhibitors of D, binding than typical antipsychotics (Meltzer et al., 1989). However, there is overlap in D, binding affinity between the two classes of antipsychotic drugs, such that clozapine and haloperidol are nearly equipotent in inhibiting SCH 23390 (a relatively selective D, antagonist) binding in vitro (Meltzer et al., 1989). Moreover, certain drugs which have been tentatively designated as atypical antipsychotics, such as melperone and setoperone, are very weak antagonists at the D, site (Meltzer et al., 1989). Finally, analyses of post-mortem material indicate that D, DA receptors are not elevated in the striatum of schizophrenic patients (Seeman et al., 1987). These data suggest that the atypical profile of clozapine cannot be attributed solely to its D, binding characteristics. It has been suggested that

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the D, receptor exists in two different states, with one form coupled to adenyl cyclase and the other form uncoupled (Andersen and Braestrup, 1986); moreover, it appears that clozapine and fluperlapine act on the adenyl cyclase-coupled state of the D, receptor (Andersen and Braestrup, 1986). It is therefore possible that atypical antipsychotics act rather selectively on the D, receptor in one state, and that D, antagonism does play a role in determining the clinical profile of atypical antipsychotic drugs. There do appear to be some differences between atypical and typical antipsychotic drugs in their effects on striatal DA metabolism. Acute administration of atypical antipsychotic drugs results in relatively small increases in various indices of striatal DA release (Bartholini, 1976a,b; ZetterStrom et al., 1985; Altar et al., 1988), in contrast to typical antipsychotic drugs. The differences between typical and atypical antipsychotic drugs in their ability to alter certain indices thought to reflect DA release and metabolism led Altar and colleagues (Boyar and Altar, 1987; Altar et al., 1988) to suggest that atypical antipsychotic drugs may act through some mechanism related to D, antagonism. However, recent in vivo dialysis studies indicate that clozapine does indeed elicit DA release in the striatum, as well as other mesotelencephalic terminal fields (Moghaddam et al., 1990a,b; see below). Moreover, discriminant function analysis of the binding characteristics of typical and atypical antipsychotic drugs to D, and D, receptors does not suggest that the ability to correctly predict the profile of an antipsychotic is enhanced by consideration of D, receptor binding in addition to D, binding (Meltzer et al., 1989). Finally, it should be noted that preliminary data suggest that antipsychotic drugs, which appear relatively non-selective in terms of D, and D, receptor affinities when measured in vitro, in contrast occupy D, receptors only to a limited degree in vivo (Farde et al., 1987, 1988, 1989a). The interaction of D, and D, receptors via changes in transduction mechanisms cannot be determined by simple examination of the binding profile of these antipsychotic drugs. D, and D, receptors interact either synergistically or antagonistically to alter final expression of a ligand’s effects (Clark and White, 1987); an example is the D,-mediated stimulation and D,-mediated inhibi-

tion of adenyl cyclase in the striatum. Seeman et al. (1989) have recently reported a novel interaction between striatal D, and D, receptors, in which pretreatment of tissue homogenates with the D, antagonist SCH 23390 prevents the ability of DA to inhibit binding of the D, antagonist raclopride, and conversely the D, antagonist eticlopride prevents the ability of DA to inhibit D, binding. Such a D,-D, link was present in putamen from Parkinson’s disease patients, but in contrast this type of interaction between the receptor subtypes was not present in putamen from a schizophrenic patient (Seeman et al., 1989); preliminary data suggest that this effect is not attributable to neuroleptic treatment of the patients. If the apparent absence of such a D,-D, link in schizophrenic brain is confirmed and is not attributable to neuroleptic treatment, it is possible that the presumptive hyperdopaminergic state in subcortical regions may represent the absence of a D,-mediated inhibition of D, receptor mechanisms. A DA D, receptor has recently been cloned and expressed (Dearry et al., 1990; Monsma et al., 1990; Sunahara et al., 1990; Zhou et al., 1990). The G protein receptor is coupled to adenyl cyclase, and Monsma et al. (1990) have demonstrated that the receptor expressed in COS-7 cells responds to DA by stimulating CAMP accumulation. While the distribution of the D, mRNA in the brain is consistent with its known localization as revealed by autoradiographic methods, the kidney appears to lack this D, mRNA. Since the kidney contains a D, receptor which stimulates phospholipase C activity (Felder et al., 1989) the lack of the mRNA encoding an adenyl cyclase-linked D, receptor suggests that other D, isoforms may exist (see Dearry et al., 1990; Monsma et al., 1990). Further molecular studies may shed additional light on the potential involvement of the DA D, receptor in mediating the effects of the atypical antipsychotic drugs. 5-HT, receptor. Virtually all antipsychotic drugs tested are at least moderately potent antagonists at the 5-HT, receptor; the exception is molindone. The affinity of antipsychotic drugs for the 5-HT, receptor has been suggested to underlie the vascular side effects of antipsychotic agents (Peroutka, 1984). It does not appear likely that antipsychotic efficacy is directly attributable to 5HT, antagonism, since pure 5-HT, antagonists have not been shown to be clinically useful in the

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treatment of schizophrenia. However, the known interactions of central serotonergic and dopaminergic systems suggest that 5-HT, antagonists may reduce enhanced DA release resulting from activation of certain mesotelencephalic DA neurons, and thus serve as an adjunctive therapy to typical antipsychotic drugs. Indeed, the ratio of 5-HT,: D, antagonism has been suggested to be the critical determinant of an atypical antipsychotic drug (see below). Accordingly, the role of 5-HT, receptors in the action of atypical antipsychotic drugs will be more fully discussed below (5-HT,-D, interactions). 5-HT, receptor. The effects of 5-HT on smooth muscle cells of the ileum are mediated by two types of serotonergic receptors, originally termed the M (morphine) and D (dibenzyline) types (Gaddum and Picarelli, 1957). The D type receptor was subsequently shown to correspond to the 5-HT, receptor, whereas the M type was designated the 5HT, receptor (Bradley et al., 1986). Over the past few years it has become apparent that the 5-HT, receptor is present in the CNS as well as peripheral tissues. Recent data indicate that clozapine binds to 5HT, sites with relatively high affinity (Hoyer et al., 1989; Schmidt and Peroutka, 1989). Moreover, ICS 205-930, a 5-HT, receptor antagonist, reverses the 5-HT-induced release of striatal DA (Blandina et al., 1989). A different 5-HT, antagonist, GR38032, partially reverses the increase in mesolimbic DA release effected by direct injection of the tachykinin analogue DiMeC7 into the ventral tegmental area (Hagan et al., 1987). These observations, coupled with the high affinity of clozapine for the 5-HT, site, have led to the suggestion that atypical antipsychotic drugs differ from typical antipsychotic drugs by virtue of interaction with the 5-HT, receptor. However, other data suggest that this hypothesis is open to question. Although GR38032 has been reported to partially reverse the increase in DA utilization in the nucleus accumbens that occurs after intra-VTA administration of a tachykinin analogue, acute administration of GR38032F does not alter either basal or haloperidol-stimulated DA metabolism in the striatum or nucleus accumbens (Koulu et al., 1989). Moreover, the loci at which 5HT, antagonists are reported to act on central DA systems are not consistent with the reported distri-

bution of 5-HT, receptors (Kilpatrick et al., 1988, 1989; Waeber et al., 1988, 1989). For example, mesolimbic DA areas such as the nucleus accumbens and olfactory tubercles have a very low density of 5-HT, receptors, and in the striatum most reports indicate that 5-HT, sites are below detectable limits (Kilpatrick et al., 1988, 1989; Waeber et al., 1988). Furthermore, in contrast to the rat, 5-HT, receptors are not present in detectable amounts in the nucleus accumbens or the striatum of the human (Waeber et al., 1989). In light of the observation that the 5-HT, antagonist ICS 205-930 reverses the 5-HT-elicited release of DA in striatal slices, it would appear that either this particular antagonist interacts with receptor sites other than 5-HT, receptors, or that the compound reverses serotonin-induced DA release through non-receptor mediated mechanisms. Recent data suggest that the putative 5-HT, agonist phenylbiguanide effects DA release in striatal slices via a DA carrier-mediated mechanism (Schmidt and Black, 1989). It also appears that some but not all 5-HT, antagonists (ICS 205-930) bind to a 5HT site positively coupled to adenyl cyclase, the 5-HT, receptor (Dumuis et al., 1988, 1989; Clarke et al., 1989). The apparent lack of specificity of certain ligands which have been suggested to be selective 5-HT, antagonists presumably underlies other discrepant results as well. For example, chronic administration of the 5-HT, antagonist MDL 73,147EF reduces the number of spontaneously active midbrain dopamine neurons and thus exerts effects similar to those of known antipsychotic drugs (Sorensen et al., 1989); in contrast, chronic administration of a different 5-HT, antagonist (BRL 43694) does not appear to decrease the number of spontaneously active dopamine neurons in the substantia nigra or ventral tegmental area (Ashby and Wang, 1990). Further study of the interaction of both typical and atypical antipsychotic drugs with 5-HT, receptors using more selective 5-HT, (and 5-HT,) agents is clearly needed before the contribution of the 5-HT, receptor to the atypical antipsychotic profile can be fully evaluated. It is significant, however, that although clozapine has a relatively high affinity for the 5-HT, receptor compared to most typical antipsychotic drugs, loxapine (another dibenzodiazepine which is a typical antipsychotic drug and results in significantly more EPS

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than chlorpromazine (Tuason et al., 1984)) binds to the 5-HT, site with approximately the same affinity as does clozapine (Hoyer et al., 1989). Thus, it appears unlikely that simply a high affinity for the 5-HT, receptor determines the atypical antipsychotic profile, although the relative affinities for 5HT, and 5-HT, (which are both present on certain neurons (Todorovic and Anderson, 1989)) may play a role. At the present time the hypothesis that the atypical profile is attributable to action at the 5-HT, receptor remains speculative. Muscarinic cholinergic receptor. One of the first attempts to explain the differences in the propensity of antipsychotic drugs to induce EPS centered on the relative potency of these drugs at the muscarinic cholinergic receptor (Miller and Hiley, 1974; Snyder et al., 1974a). Thus, antipsychotic drugs which have a relatively low incidence of EPS, such as thioridazine and clozapine, were noted to potently bind to central muscarinic receptors, whereas those antipsychotic drugs which frequently induce EPS (such as haloperidol) are relatively weak blockers of the muscarinic receptor (Miller and Hiley, 1974; Snyder et al., 1974b). However, more recent evaluation of the contribution of the antimuscarinic properties of clozapine and other atypical antipsychotic drugs suggests that while the potent antagonism of the muscarinic cholinergic receptor may contribute to the decreased incidence of EPS observed with these drugs, other factors associated with the atypical antipsychotic agents may be more critical. Ljungberg and Ungerstedt (1979) demonstrated that the contribution of antimuscarinic properties to animal behaviors which are used as screening measures in preclinical evaluations of antipsychotic drugs does not account for the differences between clozapine and haloperidol, since augmentation of haloperidol with scopolamine did not produce the same profile as clozapine. Moreover, certain putative atypical antipsychotics, such as remoxipride, lack significant affinity for the muscholinergic receptor (IC,, > 100,000) carinic (Ogren and Hogberg, 1988). Thus, it is unlikely that the ability of atypical antipsychotics to block the muscarinic cholinergic receptor is a primary factor in the lower incidence of EPS seen with these agents. While anticholinergic actions of antipsychotic drugs may have some beneficial effects in ameliorating the severity of EPS, there has been a

suggestion that there may be a therapeutic antagonism between anticholinergics used in the treatment of Parkinsonism and antipsychotic drugs (Singh and Kay, 1979); this report requires confirmation. ~xr adrenergic receptor. Virtually all known antipsychotic drugs are antagonists at the c(r receptor (see Cohen and Lipinski, 1986), and thus acutely alter noradrenergic transmission. Actions at the a, adrenoceptor are thought to underlie certain side effects (e.g., hypotension) of the antipsychotic drugs. However, Cohen and Lipinski have recently suggested that the ability of antipsychotic drugs to block c(r receptors may also be related to the antipsychotic properties of these agents. Chronic administration of antipsychotic drugs results in an upregulation of CI~receptors (Cohen and Lipinski, 1986). The increase in norepinephrine turnover elicited by haloperidol, clozapine, and thioridazine roughly parallels the clinical potency of these compounds (Richelson and Nelson, 1984) although in vitro binding data do not predict such a correlation. The differences between in vitro and in vivo antipsychotic drug potency at the c1r adrenoceptor may also cloud the interpretation of clinical findings, which indicate that the selective c(r antagonist prazosin is not clinically useful in the treatment of schizophrenia. Administration of the rl antagonist prazosin in combination with haloperidol has been reported to selectively alter DA release in the nucleus accumbens, but not in the striatum (Lane et al., 1988); this regionally specific pattern of response is similar to that seen following clozapine administration. These data have been interpreted to suggest that the actions of clozapine at the c(r receptor may contribute to the favorable motor side effect profile of the drug (Lane et al., 1988). While the preclinical data at the present time have been suggested to indicate that a1 antagonism may contribute to both the antipsychotic efficacy and reduced EPS of atypical antipsychotic drugs, clinical trials do not support this contention (Hommer et al., 1984). It has been suggested that the lack of effect of prazosin in clinical trials is somewhat limited in its ability to cross the blood-brain barrier. However, in animal studies prazosin clearly enters the brain and exerts potent actions on noradrenergic systems, albeit at a slow rate (Menkes et al., 1981). The use of other selective xl antagonists which

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readily enter the brain will help assess the contribution of the c(~ antagonism to the antipsychotic properties of neuroleptics. Sigma receptor. A number of benzomorphan opioids which have been used as analgesics possess serious psychiatric side effects, including the induction of psychotic-like states. These compounds appear to bind selectively to the sigma opiate receptor (Martin et al., 1976; Tam, 1983), which is heterogeneously distributed in the brain (Largent et al., 1984; Gundlach et al., 1986; Weissman et al., 1988; Graybiel et al., 1989). While there were suggestions that this receptor was identical to the phenylcyclidine (PCP) receptor (Sircar et al., 1986) which might therefore explain the psychotomimetic effects of the latter drug, the sigma and PCP sites are now recognized to be distinct receptors (Largent et al., 1986; Contreras et al., 1988). A number of agents which possess behavioral profiles consistent with atypical drugs have been reported in open trials to be clinically useful in the treatment of schizophrenia and yet do not produce EPS. These drugs include rimcazole, remoxipride and tiospirone (Chouinard and Annable, 1984; Lindstrom et al., 1985; Moore et al., 1985; Schwartz et al., 1985; Chouinard and Turnier, 1986; Guy et al., 1986; Jain et al., 1987). More recent data from double-blind studies suggest that tiospirone and rimcazole are without therapeutic efficacy, and these agents have been withdrawn from further testing. Remoxipride does appear to be an effective antipsychotic agent. Remoxipride (as well as rimcazole and tiospirone) binds with moderate affinity to the sigma receptor, but has an extremely low affinity for 5-HT,, xi, /I, muscarinic cholinergic, or PCP receptors (Ferris et al., 1986a,b; Taylor and Dekleva, 1987; Largent et al., 1988). Remoxipride binds with moderate affinity to the D, receptors, with an in vivo ratio of sigma:D, of 3:l (Hall et al., 1986); remoxipride has a low affinity for the D1 site. The other two sigma antagonists are essentially devoid of activity at the DA receptors. The high affinity of remoxipride for the sigma site does not appear to be shared by all atypical agents: clozapine is essentially devoid of activity at the sigma receptor (Tam and Cook, 1984). Moreover, haloperidol has a very high affinity for the sigma receptor (Tam and Cook, 1984). Thus, it appears unlikely that antagonism at the sigma site

is related to an atypical profile. Thus, the therapeutic effects of remoxipride in schizophrenia which have been reported (see below) are thought to primarily reflect its D, antagonist properties. While the atypical profile of certain antipsychotic agents does not appear likely to be attributable to interaction with the sigma receptor, it is of interest that many neuroleptics, both typical and atypical, potently bind to the sigma site. It is possible that this interaction may partially account for the antipsychotic (rather than the EPS) efficacy of these agents, since the therapeutic effects of the drug may nonetheless be mediated through functional alterations in DA neurons. Graybiel et al. (1989) demonstrated that the distribution of sigma receptors in the ventral mesencephalic DA cell group areas is heterogeneous and overlaps the distribution of D, but not D, receptors. These data may indicate that the haloperidol-displaceable sigma receptor is localized to DA neurons, on which D2 receptors are present. Consistent with this interpretation are the observations of French and colleagues, who noted that 6-hydroxydopamine lesions of the A10 DA neurons block the hyperactivity elicited by the sigma agonist ( + )SKF 10,047 (French, 1986) and that the increase in the firing rate of A10 DA neurons elicited by (+)SKF 10,047 is selectively blocked by rimcazole (Ceci et al., 1988). It is therefore possible that drugs which interact with the sigma receptor can inhibit an increase in DA neuronal firing at the cell body level, while those antipsychotic drugs which are also DA antagonists can also act at the terminal level to diminish effective DA interaction with the post-synaptic receptor. D2 tions.

dopaminergic-5-HT,

Serotonergic

interac-

As noted earlier, virtually all antipsychotic agents are potent antagonists at the 5-HT, receptor. It has recently been suggested that the ratio of 5-HT,:D, antagonism may differentiate atypical and typical antipsychotic drugs (Meltzer, 1989; Meltzer et al., 1989). Central dopaminergic-serotonergic interactions have been known for some time, and may provide an explanation for part of the atypical antipsychotic profile. Lesions of the serotonergic raphe nuclei alter DA utilization in forebrain DA terminal fields. Thus, lesions of the median raphe enhance DA utilization in the striatum and nucleus accumbens, and decrease DA utilization in the prefrontal cor-

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tex (Nicolaou et al., 1979; Herve et al., 1981). Dorsal raphe lesions also increase DA utilization in the mesolimbic site, but result in only a slight and very transient increase in the striatum (Herve et al., 1979). The enhanced DA turnover in the striatum and nucleus accumbens which occurs after raphe lesions is paralleled by an inhibition of haloperidol- and chlorpromazine-induced catalepsy (Kostowski et al., 1972) a measure thought to be a predictor of the ability of antipsychotic drugs to induce EPS. Serotonergic antagonists also prevent the haloperidol-elicited increase in DA utilization in the striatum (Vargaftig et al., 1971; ClineSchmidt and Lotti, 1974; Waldmeier and DeliniStula, 1979). In contrast, serotonin reuptake blockers and agonists potentiate the cataleptic response to haloperidol (Carter and Pycock, 1977) and potentiate haloperidol-induced increases in striatal DA utilization (Waldmeier and Delini-Stula, 1979). These data therefore suggest that serotonergic antagonists, presumably those active at the 5-HT, site (Muramatsu et al., 1988) may attenuate EPS elicited by DA receptor antagonists; this suggestion is consistent with clinical studies which found that ritanserin reduced haloperidol-induced EPS (Bersani et al., 1986; Gelders et al., 1986; Gelders, 1989). These data suggest that a relatively high ratio of 5-HT,:D, antagonism may contribute to the reduced incidence of EPS observed with some atypical antipsychotic drugs (see below). It should be emphasized that the ratio of 5-HT,:D, affinities may be the critical determinant of the degree of EPS, rather than 5-HT, binding affinity alone, since certain typical neuroleptics which produce EPS (e.g., chlorpromazine) bind with relatively high affinity to the 5-HT, receptor (see Rasmussen and Aghajanian, 1988; Meltzer, 1989; Meltzer et al., 1989). While a number of groups have suggested that the atypical profile may be related to the actions of 5-HT, receptor blockade vis-a-vis concurrent D, receptor antagonism (Rasmussen and Aghajanian, 1988; Meltzer, 1989; Saller et al., 1990) the means through which 5-HT, antagonists might contribute to the therapeutic efficacy of clozapine and other atypical antipsychotics is not clear. Clozapine appears to be effective in ameliorating negative as well as positive symptoms; current hypotheses favor a cortical dysfunction as subserving negative

sympomatology. Lesions of the dorsal raphe have been reported not to alter DA turnover in the frontal cortex (Herve et al., 1979); in contrast, median raphe lesions actually decrease DA utilization in the prefrontal cortex. Clinical reports documenting the effects of ritanserin augmentation of haloperidol therapy in treatment-resistant schizophrenics indicate that the primary benefit is an improvement in anergia, dysphoria, and anxiety, and not on thought disorder (Gelders, 1989). Ritanserin is useful as a single agent in the treatment of anxiety and depressive symptoms (Reyntjens et al., 1986). Similarly, the reduction in total BPRS scores resulting from treatment with clozapine and other putative atypical antipsychotic drugs (including those with a high 5-HT,:D, antagonism ratio) appears to reflect a greater change in anergia and anxiety than on thought disorder. Serotonergic neurons in the dorsal raphe have also been hypothesized to be a key site of action of anxiolytic agents (Thiebot et al., 1982; Iversen, 1984; Thiebot and Soubrie, 1984; see Deutch and Roth, 1990), and electrolysiological data indicate that both benzodiazepine and non-benzodiazepine anxiolytics alter the firing of 5-HT neurons in the dorsal raphe (Gallager, 1978; VanderMaelen et al., 1986). It is conceivable that the utility of clozapine in the treatment of certain negative symptoms may be partially related to the actions at 5-HT, receptors which result in antidepressant and anxiolytic actions; in contrast, the ability of clozapine to act on thought disorder may be related to actions involving cortical DA systems (see above). Finally, it should be mentioned that current concepts of the effects of interruption of serotonergic transmission on central DA systems, and the contribution of such interactions to the lower propensity of the atypical antipsychotics to produce EPS, are based on studies which have examined serotonergic modulation of perturbed (rather than basal) DA systems - for example, activated by haloperidol challenge. Cudennec et al. (1988b) have noted that stimulation of the pontine raphe nuclei results in widespread changes in local cerebral glucose utilization (LCGU), particularly in extrapyramidal areas; these changes appear to be specifically linked to serotonin release. However, electrolytic or neurotoxic lesions had virtually no effects on LCGU in any area of the brain (Cuden-

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net et al., 1988a). These data were interpreted to suggest that following chronic interruption of serotonergic transmission compensatory mechanisms become operative, or alternatively that serotonergic systems are important in the phasic, but not tonic, regulation of function. Consistent with this hypothesis are the observations that ritanserin does not antagonize haloperidol-induced dyskinesias in monkeys and in fact at high doses induces dyskinetic movements in these animals (Liebman et al., 1989); moreover, ritanserin is not effective in the treatment of tardive dyskinesia in schizophrenic patients (Mero et al., 1989). It is clear that it will be necessary to consider the sequelae of both chronic and acute administration of neuroleptics in order to understand the significance of 5-HT, receptor antagonism in reducing neurolepticinduced EPS. In vivo receptor

binding profile

A standard pharmacological strategy to identify the receptor which mediates the activity of an agent is to compare the pharmacological potencies of a series of agents with their receptor binding affinities. A significant correlation between potencies and affinities provides strong evidence that the particular receptor under question is involved in mediating the actions of the entire class of agents. For example, the therapeutic potencies of a large series of antipsychotic medications from different chemical classes (including the atypical neuroleptic clozapine) have been reported to be highly correlated with their affinities at the DA D, receptor (Creese et al., 1976; Seeman et al., 1976). In these studies, the potencies of the antipsychotic drugs were measured in terms of daily oral doses and the receptor binding affinity was measured in homogenates prepared from brain tissue. While a correlation between clinical potency and D, receptor binding was demonstrated, such a relationship could have been inadvertently overlooked because of the significant disparity among the antipsychotic drugs in bioavailability (including parameters such as absorption, metabolism, protein plasma binding, whole body distribution, and penetration of the blood brain barrier). Thus, two agents with identical receptor affinity might have markedly different oral potencies because of different rates of metabolism. Receptor binding methodologies typically use in

vitro conditions which, for technical reasons, differ markedly from the in vivo physiological state in terms of a number of parameters (e.g., assay temperature, concentration of salts in the buffer, absence of the blood-brain barrier, and the elimination of the potential interaction of the test compounds with endogenous transmitters through extensive washing procedures). Such technical aspects of receptor binding are advantageous in focusing the study on the interaction of a ligand and its receptor. However, because of the nonphysiological aspects of the assay conditions, results obtained from in vitro evaluations may not directly correlate with in vivo pharmacological state. Attempts have been made to circumvent these potential disparities by using what have been termed ‘ex vivo’ techniques. For example, Schotte et al. (1989) injected rodents with ritanserin (a selective 5-HT, antagonist) and risperidone (a potential atypical antipsychotic) to establish an in vivo receptor occupancy profile. The animals were killed and subsequently examined with radioligand binding techniques for 5-HT, and D, receptor occupancy: receptor occupancy was thus determined by an in vivo injection but measured after death. These ‘ex vivo’ techniques demonstrated a marked selectivity of risperidone for the serotonin receptor, with an ED50 ratio of 5-HT,:D, of 0.0075:2.5 mg/kg. Because the receptor occupancy by the cold drugs was established by the in vivo injection, these results may more accurately reflect the pharmacology for living human subjects than traditional in vitro receptor binding techniques. Recent advances in brain imaging methodologies have made it possible to use these techniques to measure in vivo receptor occupancy in living human and non-human primates. Such in vivo methodologies may provide a realistic assessment under physiological conditions of both affinity and bioavailability. A major goal of these neurochemical brain imaging studies is to determine which receptors are occupied by pharmacological doses of typical and atypical neuroleptic medications. The rationale is that a common pattern of in vivo receptor occupancy for the atypical agents would provide strong evidence of their mechanism of action. These studies would ideally examine a diverse number of medications with regard to their interaction with the multiple receptors which have

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been hypothesized to mediate the therapeutic actions of atypical neuroleptics. However, such studies are just beginning, and have focused on clozapine and its interaction with the dopamine D, and D, receptors. The brain imaging methodology which has been most extensively used to date for studies of atypical neuroleptics is PET (positron emission tomography). This technique measures the distribution and kinetics of uptake into brain of an intravenously administered drug radiolabeled with a positronemitting radionuclide (see Frost, 1986; Sedvall et al., 1986). For the study of atypical agents, there are two general strategies which have been employed: (1) injection of radiolabeled clozapine itself; and (2) the interaction of unlabeled (‘cold’) clozapine with specific radiolabeled probes of the dopamine D, and D, receptors. ’ C-labeled clozapine has been studied in human and non-human primate brain. Hartvig et al. (1986) showed that in monkeys there is rapid uptake of radiolabeled clozapine with the relative distribution in brain being striatum > cerebral cortex > cerebellum. In order to displace the radiolabel uptake, ‘cold’ clozapine (0.3 mg/kg i.v.) was injected about 70 min after ’ 'C-clozapine administration. However, instead of displacing the radiolabel, there was a small increase of radioactivity in striatum and cortex. The interpretation of these results is unclear, but the findings may suggest that a large percentage of “C-clozapine uptake is not displaceable and may be non-specific. PET studies of “C-labeled clozapine in human subjects (Lundberg et al., 1989) have shown a brain distribution and uptake kinetics roughly comparable to those observed in monkeys. Pretreatment with haloperidol in two subjects caused a decreased uptake in striatum and frontal cortex, which was more pronounced in striatum. Because of haloperidol’s relative selectivity for the dopamine D, receptor, these data suggest that clozapine binds in part to D, receptors, at least in the striatum. However, results in the frontal cortex are difficult to interpret because of the relatively low density of D, receptors in primate frontal cortex and because of the relatively low affinity of clozapine for the D, receptor as suggested by in vitro methodologies (Lidow et al., 1989). In summary, studies with radiolabeled clozapine are promising but difficult to interpret. The rela-

tively high uptake in frontal cortex enhances arguments that the sites of action of atypical agents involve extrastriatal regions. However, because clozapine binds to a large number of sites in the brain, it may be difficult to determine which receptors are responsible for changes in a particular region. For this reason, researchers have begun to examine the interaction of ‘cold’ clozapine with specific radiolabeled probes. With this technique, one can be more certain of the meaning of the change in the outcome variable (i.e., the specific receptor probe), although there can never be certainty that all the necessary outcome variables have been studied. Farde et al. (1987, 1989a,b) have examined D, receptor occupancy with the selective radiolabeled probe ’ 'C-raclopride. Occupancy was determined in schizophrenic patients who had been treated with a variety of antipsychotic medications for at least 1 month. Striatal uptake of radiolabel in these treated patients was compared to the average uptake of ’ ’ C-raclopride in 15 drug-naive schizophrenic patients, and the results were expressed as percent blockade induced by the drug treatment. Therapeutic doses of the antipsychotic medications were associated with D, receptor occupancy of 65-85%. This range of D, occupancy was true for all the antipsychotic drugs examined, including some which have been suggested to be atypical (thioridazine, melperone, clozapine, and raclopride). The same group (Farde et al., 1989a) also examined both D, and D, receptor occupancy during treatment with antipsychotic medications. The dopamine D, receptor was imaged with “C-labeled SCH23390, which is relatively selective for the D, receptor but also has significant affinity for the 5HT, receptor (Hyttel, 1983; Iorio et al., 1983; Hess et al., 1986). The two patients treated with clozapine (150 and 300 mg, b.i.d.) had the two lowest D, receptor occupancies (40 and 65% respectively) of all the 19 treated patients. Furthermore, among the six patients studied with “C-SCH 23390, the one patient maintained on clozapine (150 mg, b.i.d.) who was examined had the highest D, receptor occupancy (42%). In this manner, clozapine distinguished itself from the other neuroleptics by having the highest ratio of D, to D, receptor occupancy. These brain imaging studies provide promising

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preliminary data for the feasibility of in vivo receptor measurements which may help elucidate the mechanism of action of atypical neuroleptic medications. While these in vivo measurements are more ‘physiological’ than comparable in vitro studies, it is accordingly more difficult to control a large number of variables. For example, the results from Farde et al. (1988, 1989b) suggest that clozapine possesses a lower D, receptor occupancy than a typical neuroleptic like haloperidol. However, Seeman et al. (1989a) have reported that endogenous DA can displace in vivo labeling of the D, receptor by raclopride. Thus, the increased D, receptor occupancy induced by haloperidol may not be due entirely to the drug itself but also indirectly to haloperidol-induced dopamine release. While it will be of value to study more carefully this possibility, the interaction with endogenous transmitter stores clearly emphasizes the additional complexities involved in the interpretation of in vivo studies.

ELECTROPHYSIOLOGICAL ASSESSMENT OF ATYPICAL ANTIPSYCHOTIC DRUGS

In contrast to biochemical pharmacological studies of the modes of action of atypical antipsychotic drugs, there have been considerably fewer electrophysiological investigations. However, electrophysiological studies of the antipsychotic drugs have provided both important hypotheses concerning the mechanisms of action of these drugs (for example, depolarization inactivation) and served as an invaluable source of information concerning the cellular pharmacology of antipsychotic drugs. The majority of electrophysiological studies of antipsychotic drugs have involved recording from identified midbrain DA neurons. Bunney and Aghajanian and colleagues (Bunney et al., 1973; Bunney and Aghajanian, 1975) first reported the effects of acute administration of antipsychotic drugs, including clozapine, on the activity of midbrain DA neurons. In contrast to typical antipsychotic drugs, which increase the firing rate of substantia nigra (SN) (A9 cell group) DA neurons, clozapine does not increase the baseline firing rate of the DA neurons (Bunney et al., 1973; Bunney and Aghajanian, 1975). Both cloza-

pine and typical antipsychotic drugs including haloperidol increase the firing rate of Al0 DA neurons in the ventral tegmental area (VTA) (Bunney et al., 1973; Bunney and Aghajanian, 1975; Souto et al., 1978; Chiodo and Bunney, 1983; White and Wang, 1983a; Hand et al., 1987). In addition to the effects on baseline firing rate, acute administration of both typical and atypical antipsychotic drugs reverses amphetamine-induced inhibition of A9 DA neurons (Bunney et al., 1973; Bunney and Aghajanian, 1975; White and Wang, 1986). However, such effects are also observed following administration of drugs which are not antipsychotic (Bunney and Aghajanian, 1975; Aghajanian and Bunney, 1977; Chiodo and Bunney, 1983, 1985). Such a lack of correspondence between therapeutic efficacy in the treatment of schizophrenia and the ability to reverse amphetamine-elicited inhibition of midbrain DA neurons, coupled with the delayed onset of clinical efficacy of the antipsychotic drugs, led to studies of the effects of chronic administration of the antipsychotic drugs. As noted above, acute injection of haloperidol results in an increase in the firing rate and number of spontaneously firing midbrain DA neurons. In contrast, chronic administration of typical antipsychotic drugs such as haloperidol significantly decreases the number of spontaneously active DA neurons encountered in the SN (Bunney and Grace, 1978) and VTA (Chiodo and Bunney, 1983; White and Wang, 1983a). Detailed analyses revealed that the decrease in the number of spontaneously active A9 and Al0 midbrain DA neurons is attributable to these cells entering a state of depolarization inactivation (Bunney and Grace, 1978; Chiodo and Bunney, 1983, 1987; Grace and Bunney, 1986), since hyperpolarizing stimuli such as GABA induce firing of silent DA neurons, whereas depolarizing stimuli such as glutamate do not elicit activity (Grace and Bunney, 1986). Clozapine differs from typical antipsychotic drugs in that chronic administration does not induce depolarization inactivation of A9 DA neurons in the substantia nigra, but does induce depolarization inactivation in VTA Al0 neurons (Chiodo and Bunney, 1983; White and Wang, 1983b; Bunney, 1988). The time-dependent nature of the induction of depolarization blockade has been suggested to underlie the delay in onset of

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EPS and the therapeutic effects of antipsychotic drugs. In addition to electrophysiological studies of the midbrain DA neurons, recordings from DA terminal field regions such as the striatum and nucleus accumbens (NAS) have suggested that clozapine may preferentially act on the target neurons of the Al0 DA cells. Thus, chronic administration of clozapine leads to both D, and D, DA receptor supersensitivity on neurons in the NAS, but not striatum (Hu and Wang, 1988). In addition to the effects of clozapine on midbrain DA neurons and the cells in the telencephalic targets of these DA neurons, the receptor binding profile of clozapine suggests prominant actions on non-dopaminergic neurons; these actions may in part contribute to the mechanisms subserving atypical antipsychotic drugs. For example, acute administration of clozapine increases the activity of noradrenergic locus coeruleus neurons (Suoto et al., 1978; Ramirez and Wang, 1986; Rasmussen and Aghajanian, 1988). Acute clozapine administration decreases the firing rate of serotonergic neurons in the dorsal raphe (Gallager and Aghajanian, 1976). The inhibition of serotonergic neurons is not observed after acute administration of typical antipsychotic drugs, and may therefore be attributable to actions on the serotonin neuron directly, or alternatively mediated by the effects on noradrenergic systems (Gallager and Aghajanian, 1976). The involvement of serotonergic neurons in subserving the atypical profile of clozapine is aiso suggested by studies of other drugs which are 5-HT, antagonists. Thus, ritanserin increases the number of spontaneously active A9 and Al0 DA neurons (Goldstein et al., 1987) and reverses amphetamine-induced inhibition of these neurons (Goldstein et al., 1986). Administration of low doses of the mixed 5HT,:D, antagonist, ICI 169,369 (Blackburn et al., 1988; Saller et al., 1990), results in an increase in the number of spontaneously active A10 DA neurons (and, at higher doses, of A9 DA neurons) and reverses amphetamine-induced inhibition of these neurons (Goldstein et al., 1989). Chronic administration of this drug decreases the number of spontaneously active AIO, but not A9, DA neurons (Goldstein et al., 1989). These effects are therefore similar to those of clozapine. Tiosperone, another putative atypical antipsy-

chotic drug which is both a 5-HT, and D, antagonist, also appears to have preferential actions on the A10 DA neurons after acute administration (White and Wang, 1986). Tefludazine, which has been advanced as a potential atypical antipsychotic, and appears to bind to both the 5-HT, and D, receptor sites as well as the t(i adrenoceptor (Skarsfeldt and Hyttel, 1986; Svendson et al., 1986) exerts more pronounced effects on Al0 DA neurons than A9 cells after chronic administration, although it clearly decreases activity in both cell populations (Skarsfeldt, 1988). In addition to the midbrain actions of antipsychotic drugs which possess 5-HT, receptor blocking ability, these drugs can also be distinguished by their actions at other regions of the brain. Thus, clozapine (in contrast to haloperidol and sulpiride) qualitatively differs from typical antipsychotic drugs in that it blocks the suppression of prefrontal cortical neurons induced by various serotonin agonists (Ashby et al., 1989; Ashby and Wang, 1990; Ashby et al. 1990a,b); this action is consistent with the 5-HT, and 5-HT, blocking properties of clozapine. Spiperone also blocks the inhibition of prefrontal cortical neurons induced by the 5HT, and 5-HT,. agonist 1-(2,5-dimethoxy-4iodophenyl)-2-aminopropane (DOI); it therefore appears likely that the ratio of 5-HT,:D, antagonism is the important feature in suppressing the DOI-induced inhibition of cortical neurons (Ashby and Wang, 1990). This interpretation is consistent with the suggestion of Rasmussen and Aghajanian (1988) based on their evaluation of actions at the locus coeruleus, that the ratio of 5-HT,:D, antagonism may be related to the atypical profile of certain antipsychotic drugs.

REGIONAL SPECIFICITY ANTIPSYCHOTIC DRUG

OF ACTIONS

The differences between typical and atypical antipsychotic drugs may relate not only to differences in binding profile of the drugs, but also to regional specificity in site of actions. Acute administration of typical antipsychotic drugs results in more prominent effects on DA metabolism in the striaturn than in mesolimbic (e.g., the nucleus accumbens) areas, which in turn are more prominent

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than observed in cortical (e.g., medial prefrontal cortex) sites; in contrast, atypical antipsychotic drugs such as clozapine augment DA turnover to a relatively greater degree in the mesolimbic areas (Anden and Stock, 1973; Bartholini, 1976a,b; Julou et al., 1976). This may in part reflect differences in intrinsic properties of the different DA innervations (e.g., differences in basal firing rate) (see Roth et al., 1987; Wolf et al., 1987) and may reflect differences in receptor distribution across the different regions of the brain which are thought to subserve certain actions of the antipsychotic drugs. Regionally specific alterations in DA metabolism induced by administration of antipsychotic drugs becomes of considerable importance in that administration of antipsychotic drugs results in occupancy of presynaptic as well as postsynaptic receptors, and causes release of DA from DA terminals. Thus, the postsynaptic receptor blockade is antagonized to a variable degree by endogenous DA which is released from the terminal. This is further compounded by the fact that the potencies of neuroleptics for the D, receptor, as assessed by ability to displace [3H]spiperone (which binds to both D, and 5-HT, receptors), vary across different brain regions (Altar et al., 1986) as well as vary across the drugs themselves. For example, haloperidol potency for the D, site (potency order:nucleus tuberaccumbens > medial striatum > olfactory cle>cortex) is quite different from the regional clozapine profile (cortex > nucleus accumbens > olfactory tubercle > medial striatum) in that clozapine appears to be most potent in the cortex, whereas haloperidol is least potent in this region. Even if the potency at the cortical site is discounted because of the contribution of 5-HT, receptors, subcortical differences in apparent binding potency remain. These data suggest that in addition to considering the binding profile of the antipsychotic drugs, it will be necessary to clearly determine any regional differences in action: the difference between typical and atypical antipsychotic drugs may be related to regional specificity of action as much as interaction with specific types of receptors. This point of view has been recently reviewed (Delini-Stula, 1986; Ogren and Hogberg, 1988). As such, we will briefly discuss only a few recent findings. The regionally specific actions of clozapine differ from those of typical antipsychotic drugs. Cloza-

pine has long been suggested to act preferentially on mesolimbic as opposed to striatal DA systems (Anden and Stock, 1973; Bartholini et al., 1976a,b; Julou et al., 1976; Huff and Adams, 1980), although it is unclear if this action is related to antipsychotic activity (Waldmeier and Maitre, 1976). More recently, the effects of clozapine on the prefrontal cortical DA innervation has been examined. Moghaddam and Bunney (1990a,b) have reported that low doses of haloperidol selectively enhance DA release (as measured by in vivo microdialysis) in the striatal complex; at higher doses DA release is also observed in the prefrontal cortex (PFC). The selective D, antagonist (-) sulpiride, a typical antipsychotic drug, also selectively increased striatal DA release, but did not effect DA release from the PFC. Clozapine differed from both haloperidol and sulpiride: DA release in the striatal complex was not preferentially enhanced but cortical DA release was observed. Indeed, there was a trend for PFC DA release to be most sensitive to clozapine (Moghaddam and Bunney, 1990). These data suggest that the clozapine may differ from neuroleptic drugs by increasing DA release in the PFC and thus enhancing net dopaminergic activity in the cortical site. In contrast, the relatively weak effects of neuroleptics on PFC DA release, coupled with potential postsynaptic receptor blockade, may result in a net decrease in DA transmission in the PFC. These findings may relate to a large number of studies using in vivo imaging methodologies which have reported a relative hypofrontality in schizophrenic patients (Ingvar and Franzen, 1974; Buchsbaum et al., 1984; Berman et al., 1986; Weinberger et al., 1986; Paulman et al., 1990). Weinberger (1987) has hypothesized that hypofrontality may be associated with a disruption of the dopaminergic innervation of the PFC. The decrease in cortical dopaminergic activity might subsequently result in an enhancement of subcortical DA activity (Pycock et al., 1980; Simon and LeMoal, 1988; Louilot et al., 1989; Deutch et al., 1990a). Furthermore, Weinberger has speculated that the cortical DA defect leads to negative symptomatology, while the enhanced subcortical dopaminergic tone would contribute to positive symptoms. If this hypothesis is confirmed, the ability of clozapine to reduce both negative and positive symptoms may be associated with its

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ability to enhance PFC dopaminergic function while decreasing dopaminergic transmission in subcortical sites. One of the primary reasons that cortical areas have been the focus of interest in schizophrenia is because of the involvement of these areas in cognition. However, it also appears that the striatum may subserve certain cognitive functions (see Divat, 1984). There has been increasing attention to heterogeneities in striatal function over the past decade. In particular, it now appears that there is a pronounced neurochemical heterogeneity in the responsiveness of the different striatal sectors to antipsychotic drug challenge. Thus, acute neuroleptic challenge augments both DA utilization and synthesis to different degrees in different striatal sectors of the rat (Deutch et al., 1990b); the responsiveness of the particular striatal sector appears to be determined by the precise source of the mesencephalic DA afferents. In vivo microdialysis and in vivo electrochemistry have also revealed a regional heterogeneity in DA release in the striaturn in response to acute administration of antipsychotic drug (O’Connor et al., 1989; Yamamoto and Pehek, 1990). The degree to which striatal sectors thought to subserve cognitive function or those areas subserving sensorimotor function are differentially affected by antipsychotic drugs is not clear. Since the striatum is considerably larger in primate species, and since there is a more clear parcellation of striatal regions along both functional and structural bases in these species, studies on primates may help clarify the relationship between actions of atypical antipsychotic drugs and functionally and structurally distinct striatal sectors. Midbrain dopamine cell groups and actions of antipsychotic drugs. In addition to differences be-

tween haloperidol and clozapine in the ability to enhance DA release and metabolism in terminal field regions, there are also differences in terms of actions at the level of the midbrain DA cell bodies. Haloperidol only weakly increases DA metabolite concentrations in the A9 cell group in the substantia nigra (Argiolis et al., 1979; Deutch et al., 1986). Neither acute haloperidol nor clozapine administration increases concentrations of the DA metabolites’ free 3,4_dihydroxyphenylacetic acid or homovanillic acid in the DA cell body regions of the ventral tegmental area (A10 cell group) or retrorubral field (A8 cell group), although dendri-

tic release of DA is well documented (Cue110 and Iversen, 1978; Cheramy et al., 1981; Greenfield, 1985; Bradberry et al., 1989; Kalivas et al., 1989). Both haloperidol and clozapine rather robustly increase in vivo tyrosine hydroxylation (an index of DA synthesis) in both the A9 and A10 cell group regions (Argiolis et al., 1982; Deutch et al., 1986). In contrast, neither haloperidol nor sulpiride increases DA synthesis in the A8 cell group region of the retrorubral field (RRF). However, the atypical antipsychotic drug clozapine does augment in vivo tyrosine hydroxylation in the A8 cell group (Deutch et al., 1986; unpublished observations). Thus, clozapine differs from haloperidol in that the atypical drug increases DA synthesis in the A8 DA cell group, whereas the typical antipsychotic agents do not. While the significance of such differences in the metabolic activation of the three midbrain DA cell groups in response to acute antipsychotic drug administration is not clear, it is possible that activation of the A8 DA neurons (which innervate both mesolimbic and nigrostriatal areas (Deutch et al., 1988)) permits cooperative actions at striatal and mesolimbic sites, and thus prevents the emergence of certain EPS. Hypothalamic dopamine cell groups and actions of antipsychotic drugs. Clozapine and related anti-

psychotic drugs do not increase, or only minimally increase, serum prolactin levels in man and rat (Meltzer et al., 1979; Gudelsky et al., 1987). In contrast, haloperidol and other typical antipsychotic agents cause a sharp increase in circulating levels of prolactin, consistent with the action of DA as a release-inhibiting factor regulating hypophyseal prolactin. The effects of atypical and typical antipsychotic drugs on DA metabolism in the tuberoinfundibular (TI) hypothalamic DA neurons situated in the arcuate nucleus have been extensively investigated. Acute administration of typical antipsychotic drugs such as haloperidol do not increase DA turnover in the median eminence (terminal field of the TI DA neurons), nor does administration of typical antipsychotic drugs augment DA synthesis in these neurons (Gudelsky and Moore, 1976; Demorest and Moore, 1978, 1979; Gudelsky et al., 1987). However, atypical antipsychotic drugs increase both DA metabolism and synthesis in the TI DA neurons (Gudelsky et al., 1987; Gudelsky and Meltzer, 1989a), consistent with the lack of a

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prolactin surge in response to atypical antipsychotic drugs (Gudelsky et al., 1987). Gudelsky and colleagues have used the differential response characteristics of the TI DA neurons to typical and atypical antipsychotic agents as a model system in which to investigate the mechanisms subserving the actions of atypical antipsychotic drugs. In an attempt to understand the possible contribution of D, receptors to the mechanism of action of atypical drugs, the effects of pretreatment with the D, and D, agonists were examined. The D, agonists SKF 38393 and CY 2088243, but not the D, agonist quinpirole prevented the increase in in vivo tyrosine hydroxylation in the median eminence elicited by clozapine (Berry and Gudelsky, 1989; Gudelsky and Meltzer, 1989a). However, it is unlikely that the ability of atypical antipsychotic drugs to bind to the D, receptor mediates the increase in DA synthesis, since neither the D, antagonist SCH 23390 nor other atypical drugs with relatively weak binding to the D1 site increase synthesis (Gudelsky and Meltzer, 1989a). In contrast, it does appear that serotonergic systems play a role in the activation of TI DA neurons. 5,7_dihydroxytryptamine lesions of the serotonin neurons completely prevent a clozapineelicited increase in DA synthesis in the TI DA neurons (Gudelsky and Meltzer, 1989b). Similarly, pretreatment with p-chlorophenylalanine reduces the enhancement of in vivo tyrosine hydroxylation in the median eminence (Gudelsky et al., 1989b). These initial studies of the receptor determinants of antipsychotic drug actions on the TI DA neurons are therefore consistent with a role for D,-5-HT, interactions in governing the atypical profile of clozapine.

CLINICAL PUTATIVE DRUGS

INVESTIGATIONS OF ATYPICAL ANTIPSYCHOTIC

Clozapine is the only antipsychotic drug which has been convincingly demonstrated in clinical investigation to possess antipsychotic efficacy in schizophrenic patients whose symptoms are refractory to typical antipsychotic drugs, such as haloperidol or chlorpromazine. Several new agents which are putative atypical antipsychotics, and as such are

proposed to have a low incidence of EPS, have recently been developed. It is possible that some of these drugs may possess superior antipsychotic properties to conventional neuroleptics, but controlled comparison efficacy studies of these drugs have not yet been performed. In most cases, these drugs were developed on the basis of hypotheses (such as those discussed above) relating therapeutic effects to actions on specific receptors in brain regions thought to be associated with antipsychotic efficacy and side effects. Careful review of the therapeutic properties of the newer agents is therefore important because drugs which have superior efficacy or reduced side effects will provide clues to the pharmacological properties that distinguish the standard neuroleptics from novel ones which are more efficacious and have reduced incidence of side effects. Selective D, receptor antagonists There has been an interest in developing selective, potent D, receptor antagonist drugs with preferential actions on mesolimbic, compared to nigrostriatal, dopamine systems. Since clozapine has such a preclinical profile, it is anticipated that other agents with preferential actions on mesolimbic areas may be antipsychotic and yet have low EPS potential. Among such drugs are two drugs which are selective D, antagonists (sulpiride and raclopride) and one drug which is a relatively selective D, antagonist but which also interacts with sigma receptors (remoxipride). Sulpiride. Sulpiride is a selective D, dopamine receptor antagonist which has been extensively documented to be an effective antipsychotic drug. However, it has not been definitely shown to produce less EPS than standard neuroleptics or be more efficacious than typical antipsychotics (Ishimaru et al., 1971; Nishiura, 1976; Mjelke et al., 1977; Bratfos and Haug, 1979; Edwards et al., 1980; Rao et al., 1980; Alfredsson et al., 1984; Harnryd et al., 1984; Gerlach et al., 1985; Alfredsson and Wiesel, 1989; Wik et al., 1989). While it seems relatively clear that sulpiride does result in EPS, the relative clinical efficacy of sulpiride is somewhat unclear: sulpiride is a hydrophilic compound and therefore appears to penetrate the blood brain barrier poorly (Alfredsson et al., 1984). Raclopride. Open studies with raclopride indicate it is an effective antipsychotic and does not

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produce EPS (Cookson et al., 1989; Farde et al., 1989b); raclopride was reported to produce akathisia in about one quarter of the patients tested. A multi-center double-blind fixed-dose comparison study is now in progress to determine raclopride’s relative efficacy and EPS profile compared to standard neuroleptics. Remoxipride. Preclinical studies predict that remoxipride has a low propensity for induction of EPS (Gerlach and Casey, 1990). Open clinical studies with remoxipride have supported this prediction and suggest that remoxipride is an effective antipsychotic with a low propensity for induction of EPS (McCreadie et al., 1985; Laursen and Gerlach, 1986; Den Boer et al., 1987). The initial double-blind study comparing remoxipride to thioridazine indicated that remoxipride possesed antipsychotic properties but was slightly less effective (McCreadie et al., 1988). However, recent double-blind comparison studies indicate antipsychotic efficacy comparable to haloperidol, but with a much reduced incidence of EPS (Ahlfors et al., 1989; Beckman et al., 1989; Lapierre et al., 1989; Den Boer et al., 1990); extensive scrutiny of these reports and others in progress will clearly be a focus of researchers and clinicians studying the modes of action of atypical antipsychotic drugs. Partial D, receptor agonists It has been suggested that partial DA agonists with high affinity but low efficacy at D, receptors can modulate dopamine function by reducing dopamine activity when it is excessive and enhancing activity when release is decreased (Carlsson, 1988). Such drugs have the potential to alleviate both positive and negative symptoms while producing less EPS (Coward et al., 1989). Two partial D, agonists currently in clinical trials are terguride and OPC-4392. Terguride has been tested in an open study involving 11 schizophrenic patients and found to be clinically effective in relieving both positive and negative symptoms (Olbrich and Schanz, 1988). Another D, receptor agonist, OPC-4392, was also evaluated in an open investigation and noted to have antipsychotic properties (Gerbaldo et al., 1988). Both partial agonists were reported to have favorable side effect profiles. Dopamine agonist augmentation treatment A large number of studies have attempted determine if dopamine agonist administration

to to

schizophrenic patients maintained on neuroleptics (dopamine agonist augmentation) would result in an improvement in negative symptoms. Current use of this strategy is based upon elaborations of the dopamine hypothesis which suggest that either increased or decreased DA activity, depending on the specific brain region examined, may occur in schizophrenia (Berman et al., 1986; Weinberger et al., 1986; Weinberger, 1987). In particular, it has been postulated the negative schizophrenic symptoms may be associated with decreased dopamine function in the prefrontal cortex, while positive symptoms may be due to dopamine excess in subcortical (mesolimbic) dopamine sites (Weinberger et al., 1986; Weinberger, 1987). An outgrowth of this hypothesis has been attempts to develop a treatment strategy for schizophrenia based on reduction of subcortical, but augmentation of cortical, dopamine function. Amphetamine. A large scale cooperative Veterans Administration investigation studied the treatment of 462 ‘withdrawn, chronic, apathetic’ male schizophrenics with a combination of chlorpromazine with amphetamine, trifluperazine, imipramine, isocaboxazid, or placebo. All patients except those on amphetamine improved; however, in no group was more overall improvement seen than in the chlorpromazine plus placebo group (Casey et al., 1961). A more recent study reported a beneficial effect of administration of D-amphetamine in doses up to 50 mg/day to schizophrenic patients, 73% of whom were receiving neuroleptics (Cesarec and Nyman, 1985). Approximately two thirds of the patients experienced significant improvement in mood and concentration, and reported decreased anxiety; 69% showed better overall function. Nine of 17 patients with prominent negative symptoms improved. Bromocriptine. The usefulness of the direct DA agonist bromocriptine in schizophrenic patients has been examined by several groups. The results have been inconsistent; this may reflect variations in dose and whether patients were maintained on neuroleptics (Roehrich et al., 1987). However, a study by Cutler et al. (1984) may be instructive. In a double-blind, placebo-controlled crossover study on schizophrenic patients maintained on neuroleptics, significant clinical improvement with acute bromocriptine treatment was reported (Cutler et al., 1984).

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L-Dopa. Open studies of small sample size without control groups have generally reported an increase in psychotic symptoms when L-dopa is given to patients not maintained on neuroleptics. However, there have been at least six open trials conducted in Japan of r,-dopa (400-800 mg/day) in 290 schizophrenic patients maintained on antipsychotic drugs. Deterioration was noted in less than 5% of the patients; improvement was reported in one-third to two thirds of patients, and typically involved negative symptoms (Ogura et al., 1976). In addition, there have also been four controlled studies of L-dopa in medicated schizophrenic patients which suggest L-dopa may improve negative symptoms (Buchanan et al., 1975; Gerlach and Luhdorf, 1975; Inanaga et al., 1975; Alpert et al., 1978). D, receptor agonists. There has been an increased interest in the possible role for D, receptors in the etiology and treatment of schizophrenia. This has been due, in part, to the relatively extensive brain distribution of D, receptors, particularly in the human cortex (Dawson et al., 1987; Cortes et al., 1989); in contrast, D, receptor density is considerably lower (Camus et al., 1986; Lidow et al., 1988; Camps et al., 1989). Moreover, recent data concerning the functional interaction between D, and D, receptors (see above) have also led to an interest in the role of D, receptors in schizophrenia. In this context, it may be desirable to administer antipsychotic drugs which possess a relatively high affinity for the D, receptor in an attempt to modulate D, function. There has been one published investigation on the therapeutic effects of a D, receptor agonist (Davidson et al., 1990). Ten patients who failed to benefit from 4 weeks of treatment with haloperidol were randomly assigned to one of two groups in a D, augmentation study. One group received the D, agonist SKF-38393 (250 mg, b.i.d.) and haloperidol (20 mg, q.i.d.), whereas the second group received placebo augmentation of haloperidol for 4 weeks. During the subsequent 4 weeks the two groups were crossed over. In three of the ten patients, SKF-38393 treatment resulted in a decrease in BPRS score, while in two patients an increase in BPRS scores of approximately 20% was observed. Although the findings of this investigation did not suggest that D, augmentation is an effective

therapeutic strategy, the results are clearly preliminary. A number of factors associated with this approach remain to be resolved (e.g., bioavailability characteristics). Moreover, there are some preclinical data suggesting that D, augmentation may be expected to produce therapeutic benefits. As such it may be premature to abandon this treatment strategy. It will be desirable to examine a larger cohort which includes non-refractory patients, and to determine the effects of a wider dose-range of SKF-38393. S-HT, receptor antagonists There has been a recent focus on the development of pharmaceutical agents for the treatment of schizophrenia which are both potent D, and 5HT, receptor antagonists. This has been primarily motivated by observations suggesting that 5-HT, receptor antagonists may have anxiolytic and antidepressant properties and thereby improve negative symptoms, and by data suggesting that 5-HT, antagonists may reduce neuroleptic-induced EPS when added to neuroleptics (Gelders, 1989). Ritanserin. Ritanserin is a very effective central 5-HT, antagonist which may be useful in the treatment of anxiety and depressive disorders (Reyntjens et al., 1986). Preliminary data suggest that ritanserin may possess modest antipsychotic efficacy when given as a single agent (Gelders, 1989). Setoperone. This agent is a potent 5-HT, antagonist and is a specific LSD antagonist in laboratory studies. In preliminary open trials, setoperone was reported to possess antipsychotic efficacy for both negative and positive symptoms, and exhibit a low EPS profile (Ceulemans et al., 1985). No direct efficacy comparison studies to other antipsychotics have been done. Clinical use of this compound is limited by poor bioavailability. Melperone. In vitro binding studies indicate that melperone has moderate affinity for the 5-HT, receptor but low affinity for the D, and D, receptors. However, recent PET studies suggest that there is substantial D, occupancy in vivo by melperone (Farde et al., 1989). The therapeutic efficacies of melperone and thiothixene were compared in a group of 8 1 female schizophrenic patients. While approximately equal clinical efficacy was reported, thiothixene produced more EPS (Bjerkenstedt et al., 1987, 1989).

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Amperozide. This agent has low D,, low D,, and moderately high 5-HT, receptor affinity (Meltzer, 1989; Christensson and Bjork, 1990; Svartengren and Simonsson, 1990). Behavioral studies indicate that amperozide reduces mesolimbic, but not striatal, DA function, and antagonizes 5-HT,receptor mediated events (Gustafsson and Christensson, 1990). Electrophysiological investigations indicate that amperozide has complex effects on mesolimbic dopamine neurons including changes in firing pattern and excitability, and protection against reversible hypofrontality (Grenhoff et al., 1990). Open clinical studies suggest that amperozide may have antipsychotic efficacy (unpublished data, Sandoz Pharmaceuticals). 5-HT,

receptor

antagonists

Recent reports have suggested that 5-HT, receptors may play a role in the pathogenesis and treatment of psychotic symptoms (Tricklebank, 1989; see above). Accordingly, there have been recent clinical trials of the 5-HT, antagonist odansetron (GR 38032). Ondansetron. The only 5-HT, receptor antagonist which is currently being tested clinically, to our knowledge, is ondansetron. Open clinical trials in schizophrenic patients using fairly high doses (16 mg, b.i.d.) have not indicated antipsychotic properties (Joanne Bell, Glaxo, personal communication). However, since very low doses of 5-HT, antagonists appear to have behavioral effects in experimental animals which are consistent with antipsychotic potential, and indeed behavioral response to 5-HT, antagonists have been reported to follow an inverted U-shaped function (Costa11 et al., 1987) it is possible that the doses used in clinical trials were too high. Additional clinical investigations with odansetron at lower doses are planned.

failed to reveal antipsychotic efficacy of rimcazole, and rimcazole is no longer in clinical testing (T. Dren, Burroughs Wellcome, personal communication, Feb. 1990). It is important to note, however, that rimcazole, while a selective sigma antagonist, is not very potent. As such, future studies using selective and potent sigma antagonists will clarify the situation. Noradrenergic

Cholinergic Sigma opiate receptor

antagonists

The possible role for sigma receptors in psychotic disorders has been investigated by evaluating the efficacy of the sigma antagonist rimcazole. Four open clinical trials originally suggested that rimcazole treatment resulted in marked improvement in approximately 50% of the schizophrenic patients tested; EPS were virtually absent (Guy et al., 1983; Chouinard and Annable, 1984a; Schwartz et al., 1985). However, subsequent double-blind studies

receptor

antagonists

and agonists

Biochemical evidence suggestive of abnormal noradrenergic function in schizophrenia has been recently reviewed (see Van Kammen and Gelernter, 1987). These data suggest that intervention with pharmacological agents which alter noradrenergic transmission may be useful in the treatment of schizophrenia. /I receptor antagonists. Controlled studies have generally indicated that fi adrenergic antagonists are not very effective antipsychotics. More recent evidence suggests that the beneficial effects of propranolol in schizophrenic patients is primarily due its ability to reduce akathisia (Tamminga and Gerlach, 1987). c(i receptor antagonists. The one clinical trial which has evaluated the efficacy of the a, receptor antagonist prazosin in schizophrenic patients did not demonstrate antipsychotic effects (Hommer et al., 1984). c(~ receptor agonists. Several investigations have examined the efficacy of the CQ agonist clonidine in schizophrenic patients. At appropriate doses clonidine reduces noradrenergic activity by acting at a,-adrenergic autoreceptors. The results of these clinical trials with clonidine indicate that as a single agent clonidine has only modest therapeutic effects (Freedman et al., 1982; Van Kammen and Gelernter, 1987; Fields et al., 1988). antagonists

A recent review of the literature has led to the suggestion that alterations in cholinergic function involving muscarinic cholinergic receptors may be involved in schizophrenia; specifically posited is the relationship between increased muscarinic cholinergic activity and negative symptoms, and conversely between decreased cholinergic activity and positive symptoms (Tandon and Greden, 1989). Muscarinic antagonists, which are commonly used to treat EPS, have been reported to have an

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adverse effect on the therapeutic actions of neuroleptics, particulary in relation to positive symptoms (Singh and Smith, 1973; Singh and Kay, 1979; Johnstone et al., 1983). However, in contrast to these reports there are some data suggesting that anticholinergic medications, such as trihexiphenidyl, may ameliorate negative symptoms (Tandon and Greden, 1987). In addition, several reports of anticholinergic drug abuse by schizophrenic patients have suggested that such abuse may be attributable to the mood elevating properties of these drugs (see Tandon and Greden, 1989). While clozapine is clearly a potent cholinergic antagonist, this property of the drug does not appear to be sufficient to account for the lack of EPS with clozapine (see above). However, the degree to which the anticholinergic properties of clozapine contribute to its action on negative symptoms remains to be determined. Dopamine D, and serotonin 5-HT, receptor antagonists In light of the fact that clinical trials of 5-HT, antagonists have not been very promising (see above), recent attention has focused on agents which are antagonists at both 5-HT, and D, receptors, and on serotonin antagonist augmentation strategies. Risperidone. Risperidone has been well characterized as a very potent serotonin 5-HT, and D, receptor antagonist which acts at central sites (Leysen et al., 1988; Monfort et al., 1989). Open trials in psychotic patients have indicated risperidone has substantial antipsychotic properties with a decreased propensity for induction of EPS compared to standard neuroleptics; risperidone appeared to improve both positive and negative symptoms (Castelao et al., 1989; Monfort et al., 1989). Recent data also suggest that risperidone may be schizophrenic effective in treatment-resistant patients. In a single-blind study, risperidone was shown to improve positive, negative and dysthymic symptoms in approximately 60% of treatmentresistant chronic psychotic patients (Gelders et al., 1988). A more recent double-blind investigation compared the effects of risperidone to haloperidol in 42 treatment-resistant schizophrenic patients: risperidone was found to be superior to haloperidol in improving both positive and negative symptoms, but produced less EPS (Peuskens et al., 1989).

Zotepine. Zotepine is a potent antagonist at central D,, D,, and 5-HT, receptors. Initial open clinical studies reported antipsychotic efficacy equal to haloperidol, chlorpromazine, or thioridazine, but with a low incidence of EPS (Uchida et al., 1979; Yamawaki, 1987). Zotepine has not been tested in treatment-resistant patients. Tiosperone. This drug is a potent D, and 5-HT, antagonist. However, ongoing clinical studies in schizophrenic patients have been disappointing when tiosperone has been compared to haloperidol and thioridazine (Robert Pyke, personal communication, Feb. 1990). Definitive studies of the therapeutic efficacy of tiosperone remain to be completed. Serotonin antagonist augmentation strategies The hypothesis that 5-HT, receptor antagonism may be of clinical benefit in schizophrenia has led to studies designed to determine if administration of 5-HT, antagonists to schizophrenic patients maintained on antipsychotic drugs (i.e., serotonin antagonist augmentation) is helpful in treatmentresistant patients. An open study indicated that augmentation with cyproheptadine (a serotonin antagonist) to haloperidol-treated schizophrenic patients reduced BPRS scores in 40% of patients; the mean BPRS decrease primarily reflected a decrease in negative symptoms (Silver et al., 1989). Two controlled studies (Gelders et al., 1986; Awouters et al., 1988) have suggested that ritanserin (a 5-HT, receptor antagonist) augmentation of neuroleptic-treated schizophrenic patients results in improvement in negative symptoms and also reduces EPS. However, Meco et al. (1989) were unable to replicate these findings. These preliminary observations suggest that 5-HT receptor antagonism may be helpful in reducing anxiety and depression, and other components of the improvement which is reported as a reduction in the negative symptom complex in schizophrenia. D, and 5-HT, receptor antagonists This receptor binding profile of clozapine indicates relatively high potency of the atypical at D, and 5HT, receptors, with somewhat less affinity for the D, receptor. As such, putative antipsychotic drugs which block both D, and 5-HT, receptors are being developed for testing. The chemical structure and pharFluperlapine. macological profile of this agent are similar to

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clozapine. Fluperlapine has an affinity for D, receptors approximately equal to clozapine, but exhibits an affinity for the D, receptor which is lowe#r than that of clozapine; fluperlapine binds with’high affinity to the 5-HT, receptor. In open clinical trials fluperlapine was found to be an effective antipsychotic while rarely producing EPS (Woggon et al., 1984, 1985). No direct comparison studies to other antipsychotic drugs have been performed. Fluperlapine has been withdrawn from further clinical study because, like clozapine, it produces agranulocytosis.

COMMENT

The mechanisms by which clozapine exerts therapeutic effects yet does not result in concomitant extrapyramidal side effects remain elusive. Clozapine does not appear to have any unique actions on dopaminergic, serotonergic, cholinergic, adrenergic, or sigma receptors which can account for its superior antipsychotic efficacy and lack of EPS. Accordingly, it has been necessary to attempt to determine properties of a group of putative atypical antipsychotic drugs which contribute to the favorable clinical profile. Such an approach is clearly clouded by the fact that many of the agents classified as atypical antipsychotic drugs at the present time have not undergone appropriate rigorous clinical evaluation; there have been a number of drugs which in open trials have appeared be effective antipsychotics only to be shown in double-blind studies to lack therapeutic efficacy. Nonetheless, at the present time the best assessment of the factors which contribute to the clinical profile of clozapine are derived from an evaluation of a number of agents which are putative atypical antipsychotic drugs. At the present time, given that all known antipsychotic drugs are D, antagonists, and given the preliminary data suggesting that raclopride and remoxipride are antipsychotic drugs, one hypothesis concerning the mode of action of atypical antipsychotic drugs would posit D, receptor antagonism may be sufficient to account for the atypical profile. However, since other selective D, antagonists such as sulpiride do not appear to be atypical antipsychotic drugs, we hypothesize that

the atypical profile may be subserved by D, receptor antagonists which interact with different isoforms of the D, receptor, the relative expression of which quantitatively differs across brain regions. At the present time it is not known if the different D, isoforms have different binding profiles. The intracellular events triggered by interaction of antipsychotic drugs with the receptor may also differ according to D, isoform. Given that the relative bioavailability of the antipsychotic drugs differs across regions of the brain, and that features intrinsic to the DA neurons (e.g., firing rate, presence or absence of certain autoreceptors) vary across regions, the effective transduction of the interaction of a particular drug with different D, isoforms would be expressed by differences in intracellular processes in the neuron on which the receptor(s) reside. While actions at a D, receptor subtype may be sufficient to determine the atypical profile, it is likely that an atypical antipsychotic profile can be achieved through other means as well. Meltzer has hypothesized that the ratio of D,:5-HT, receptor antagonism may be a key feature in determining the atypical profile (Awouters et al., 1988; Rasmussen and Aghajanian, 1988; Meltzer, 1989; Meltzer et al., 1989). Consistent with this hypothesis are data which suggest that augmentation of D, antagonists with 5-HT, antagonists decreases EPS and ameliorates negative symptoms. Antipsychotic drugs which possess both D, and 5-HT, receptor antagonism appear to be more effective in the treatment of the negative symptom complex. These findings suggest that concurrent D, and 5-HT, receptor antagonism may provide a means through which an atypical profile can be achieved. If future clinical trials confirm the clinical superiority of 5HT, antagonist augmentation of conventional neuroleptics over typical antipsychotic drugs alone, such interactions may provide clues as to the mechanisms by which certain D, antagonists differ from other D, antagonists; for example, concurrent 5-HT, and D, antagonism may result in changes in intracellular processes in postsynaptic target cells which mimic those seen in animals treated with raclopride or clozapine. At this time these two hypotheses of mechanisms subserving atypical antipsychotic drug action (actions at D, receptor subtypes and interactions between 5-HT, and D, receptors) appear to be

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best supported by available evidence. Although there are findings which are consistent with a role for c(i adrenoceptors, as well as 5HT,, D,, and sigma receptors, these findings are sufficiently limited as to delay formation of a specific hypothesis concerning the roles which these receptor systems may play in determining the atypical profile. Finally, it should be mentioned that the interactions of antipsychotic drugs with currently undefined (or unexamined) receptor systems may subserve the atypical profile. For example, Cl -943, a recently described compound which has an animal behavior and electrophysiological profile consistent with an antipsychotic drug (Heffner et al., 1989; L.T. Meltzer et al., 1989) has not been shown to bind to any known receptor (Pugsley et al., 1989). Although the potential binding of Cl-943 to 22 different receptor types has been examined, the IC,, for all of these sites is > 10,000 nM (Pugsley et al., 1989). Nonetheless, systemic administration of Cl-943 increases both DA and 5-HT metabolite concentrations in the striatum (Pugsley et al., 1989) inhibits one-way avoidance (Heffner et al., 1989) and increases the number of spontaneously active A10 (but not A9) DA neurons after chronic administration (L.T. Meltzer et al., 1989). These studies suggest that receptors other than those commonly examined in binding studies of potential antipsychotic drugs may contribute to some of the affects of antipsychotic drugs. The difficulties in assessing the contribution of neurotransmitter receptor systems to the atypical antipsychotic drug profile is attributable not only to a relative paucity of direct information concerning these systems, but also to flaws in the approaches to the study of the determinants of the atypical drug profile. Considerable efforts are being directed toward elucidation of the mechanisms subserving the ability of atypical antipsychotic drugs to act specifically to reduce psychotic symptomatology yet not produce EPS. The basic goal of most experimental approaches to the question of the mechanisms subserving the action of clozapine and other atypical neuroleptics is identification of the relevant receptor or receptors with which atypical, but not typical antipsychotic drugs interact. However, certain factors suggest that modifications to current approaches to this question may aid in determining the critical features subserving the atypical profile.

The determination of the binding profiles of typical and atypical antipsychotic drugs, and subsequent comparisons of these profiles, has led to several hypotheses concerning the mode of action of atypical antipsychotic drugs. However, there are exceptions to virtually every scheme proposed to date, in that certain typical antipsychotic agents will possess the proposed binding profile, or alternatively certain atypical antipsychotics will not possess the predicted profile. Most binding profiles are determined using a particular ligand in a particular central nervous system site, in most cases the tissue being removed from experimental animals such as the rat. It is well appreciated that different ligands can result in different binding profiles, one critical factor being the degree of specificity of the ligand for the receptor in question. Less well understood are the contributions made to the apparent binding profile by determinants of the brain region being examined, species differences in receptor characteristics, and the tissue condition (normal as opposed to pathological or iatrogenically modified). Since the contributions of such factors are not often discussed, we suggest that it may be desirable to attempt to follow certain approaches in the study of neurobiological mechanisms subserving the atypical antipsychotic profile. The assessment of the binding profile should be made in tissue from multiple brain regions, chosen on the basis of proposed involvement in the disorder. Thus, in schizophrenia it would appear that regions such as the striatum, nucleus accumbens and other mesolimbic sites, and cortex would be appropriate sites; in contrast, there is little to suggest, for example, that the red nucleus or basis pontis would be particularly relevant. The examination of multiple tissue sites becomes important because there appear to be regional heterogeneities in the apparent binding profiles of various receptors. For example, D, receptors in the cortex appear ‘atypical’ when compared to striatal or mesencephalic D, receptors (Thierry et al., 1986; Sesack and Bunney, 1989). Such regional heterogeneities may reflect different (as yet unappreciated) subtypes of receptors. In the case of the D, receptor, regional differences may be related to alternative splicing of the D, gene and resultant multiple forms of the receptor. At the present time it appears that the relative expression of the D,,

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and D,, mRNAs may differ regionally, although it does not appear that there are any regions in which only one form is expressed (Dal Toso et al., 1989; Giros et al., 1989; Meador-Woodruff et al., 1989; Mengod et al., 1989; Monsma et al., 1989). Another important factor to be considered is that the distribution of receptors on given neuronal populations may vary across different brain regions. For example, in the striatum certain electrophysiological data are consistent with both D, and D, receptors residing on the same neurons; this awaits experimental verification using anatomical techniques. While interaction of a particular ligand will be recognized in tissue in which only one receptor is present on a given neuronal population, the effective interaction of the endogenous ligand (DA) may well be different when both receptors are present on the same neuron, in light of receptor-receptor interactions (Fuxe et al., 1986). In most cases our original knowledge of the binding profile of a particular antipsychotic drug is based on examination of brain tissue from the prototypical laboratory animal, the rat. Yet it is clear that it is difficult to extrapolate from one species to another. For example, the DA innervation of the primate cortex is considerably more extensive than the regionally restricted pattern of DA innervation of the rat cerebral cortex (Lewis et al., 1987, 1988; Berger et al., 1988; Gaspar et al., 1989). Moreover, the distribution of D, and D, receptors differs beween rat and monkey (Sasvasta et al., 1986a,b; Richfield et al., 1987; Camps et al., 1989; Cortes et al., 1989; Lidow et al., 1989). Similarly, Pazos et al. (1984a) have reported the presence of mesulergine (5-HT,) receptors’ in rat but not human cortex, and there is an apparent receptors in human brain as absence of 5-HT,, well (Martial et al., 1989). The determination of the binding profile of a prospective antipsychotic drug is typically made on tissue removed from an untreated animal. The therapeutic effects of antipsychotic drugs are delayed; this suggests that the actions of the antipsychotic drugs are mediated through receptors which are modified by continued exposure to antipsychotic agents. Moreover, it is conceivable that the selectivity that certain ligands have for a particular receptor may be lost following chronic treatment. Thus, receptor binding profiles determined by examination of tissue chronically exposed to an

antipsychotic drug may differ from the profile obtained using normal tissue. The binding profile of antipsychotic agents is generally examined in tissue from experimental animals, or alternatively on post-mortem samples from normal subjects without evidence of central nervous system disease and without history of psychiatric disorder and chronic neuroleptic treatment. However, animal studies suggest that chronic neuroleptic treatment may not only change receptor density and affinity, but may also alter both the normal density or pattern of dendritic arborization and synaptic arrangement (Benes et al., 1985; Klintzova et al., 1989; Meshum and Casey, 1989). In addition, there are indications that the disease process associated with schizophrenia may result in neuropathological changes which are independent of neuroleptic treatment (Benes and Bird, 1986, 1987; Kirch and Weinberger, 1986; Benes et al.. 1987; Kleinman, 1988). The effective sites of interaction of antipsychotic drugs may therefore be effectively altered by the loss of certain receptors located on affected neuronal populations, or via indirect effects mediated by changes in follower cells. Thus, the binding profile in tissue from patients suffering from schizophrenia may differ from that observed in experimental animals, due to changes related to either the disease process or pharmacological therapy. Similarly, changes related to disease process or which are iatrogenic in nature may alter either receptor or transmitter ligand gene expression. For example, recent data have suggested that in the normal human substantia nigra CCK mRNA is not present (Palacios et al. 1989). However, in the substantia nigra of schizophrenic patients treated with neuroleptics there appears to be a relatively high number of CCK transcripts (Schalling et al., 1989). It is not clear if the differences between the control tissue and that from schizophrenic patients is attributable to chronic neuroleptic treatment or the schizophrenic process. Receptor measures at the present time focus on the density or affinity of receptors. However, the typical and atypical antipsychotic drugs may differ in their ability to induce changes not only in the number and affinity of receptors, but also changes in the dynamics of receptor turnover. It is conceivable that alterations in the turnover, rather than steady-state concentration of receptor may be

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differentially altered by atypical as opposed to typical antipsychotic drugs. While most attention in the search for mechanisms subserving atypical antipsychotic actions has focused on receptor binding profile, the functionally significant event is the transduction of the ligand-receptor interaction to the intracellular processes of the neuron. Transduction mechanisms have not been intensively investigated in relation to the modes of action of atypical antipsychotic drugs. Recent data suggest that receptors may have regionally distinct transduction mechanisms. For example, De Keyser et al. (1989) have suggested that G protein coupling of the D, receptor differs in the prefrontal cortex and in the striatum; this may in turn be related to different forms of the D, receptor. The factors discussed above suggest that in order to define the mechanisms by which atypical antipsychotic drugs exert therapeutic efficacy without the propensity for induction of extrapyramidal side effects it will be necessary to simultaneously approach the problem on several fronts. The determination of the binding profiles of atypical agents will require rigorously defined and selective ligands. Assessment of binding characteristics should be performed in multiple brain areas; this will necessitate the complementary approaches of binding studies performed in both tissue homogenates and in tissue slices (autoradiographic assessment). The tissue examined should be derived not only from experimental animals such as the rat, but in addition tissue from primate species (including man) should be examined. Moreover, since pharmacological treatment may well modify the response characteristics of certain receptors, it may be instructive to examine the binding profiles of various antipsychotic agents in animals subjected to chronic neuroleptic treatment. Determination of receptor turnover (which can now be accomplished using molecular biological approaches as well as by the use of agents for the irreversible alkylation of certain receptors in vivo) will add to our understanding of the modes of action of both typical and atypical antipsychotic drugs. As mentioned above, it is possible that the disease process itself may result in structural brain changes. The agreement of patients (and family) to the use of post-mortem brain tissue will facilitate neuropathological determinations and may effec-

tively add to our ability to define the critical binding characteristics of atypical antipsychotic drugs. The limited availability of post-mortem tissue indicates that alternative approaches to the problem involving in vivo assessment will be required; such approaches include positron emission tomography, single photon emission computed and nuclear magnetic resonance tomography, spectroscopy. In addition to studies of receptors, additional attention will have to be devoted to elucidation of actions on transduction mechanisms. Moreover, since treatment may modify gene expression of various endogenous ligands, enzymes, and transduction proteins, examination of the effects of atypical antipsychotic drugs on such changes will have to be made. Data derived from the above approaches will add to our understanding of the modes of action of atypical antipsychotic drugs. However, it will be necessary to exercise caution in attempting to relate observed differences on various biochemical or electrophysiological measures between typical and atypical antipsychotic drugs to critical differences related to clinical efficacy or side effect profile. There will undoubtably be many observed differences between typical and atypical antipsychotic drugs which are epiphenomena to those critical differences related to efficacy and side effects. In light of the often repeated caveat that schizophrenia is a group of disorders rather than a single entity, it is also important to realize that there may be more than one type of atypical antipsychotic drug profile (for example, lack of EPS and superior efficacy vs. lack of EPS and equal efficacy in reference to neuroleptic drugs). In addition, there may be more than one neurobiological mechanism through which an atypical antipsychotic agent operates.

ACKNOWLEDGEMENTS

This work was supported by the Veteran’s Administration National Center for Schizophrenia Research Center at the West Haven Veteran’s Administration Medical Center. This work was also supported by MH-45124 and by a grant from the Scottish Rite Schizophrenia Research Program.

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