Half a century of antipsychotics and still a central role for dopamine D2 receptors

Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 1081 – 1090 www.elsevier.com/locate/pnpbp

Half a century of antipsychotics and still a central role for dopamine D2 receptors Shitij Kapur*, David Mamo Schizophrenia Program, CAMH, Toronto, ON, Canada PET Centre, CAMH, Toronto, ON, Canada Department of Psychiatry, University of Toronto, Toronto, ON, Canada Accepted 9 September 2003

Abstract A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a ‘‘one-size-fits-all polypharmacy-in-a-pill’’ approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients’ presenting psychopathology. D 2003 Published by Elsevier Inc. Keywords: Atypical antipsychotics; Dopamine D2 receptors; Schizophrenia; koff; Receptor occupancy; Motivational salience

1. Introduction The year 2002 marks exactly half a century since the first published report of the use of an antipsychotic for a psychiatric indication. A number of informative lessons can be learnt from a review of this history and some of the salient points will be discussed in this paper. Following the accidental discovery of antipsychotics, subsequent advances in the pharmacological therapies of psychotic

Abbreviations: EPS, extrapyramidal side effects; koff, equilibrium dissociation constant of a ligand at its receptor; PET, positron emission tomography. * Corresponding author. PET Centre, Clarke Division of the CAMH, 250 College Street, Toronto, ON, Canada M5T 1R8. Tel.: +1-416-5358501; fax: +1-416-260-4164. E-mail address: [email protected] (S. Kapur). 0278-5846/$ – see front matter D 2003 Published by Elsevier Inc. doi:10.1016/j.pnpbp.2003.09.004

symptoms have come through modifications and improvements of previous drugs. Consequently, action at the dopamine D2 receptors remains central to antipsychotic action of even the newer antipsychotics. This is not to suggest that action at other receptors does not play a role in schizophrenia and the treatment of psychotic disorders. Rather, the legacy of the dopamine D2 receptor antagonists continues to pervade our pharmacotherapeutic armamentarium for psychotic disorders, and as will be discussed in more detail later, modulation of dopamine D2 receptor remains a necessary and even sufficient condition for antipsychotic action. Since the serendipitous discovery of chlorpromazine and reserpine, advances in psychopharmacology, cognitive neuroscience and functional brain imaging techniques have allowed us to probe deeper into the action of antipsychotic drugs both at a molecular level as well as the neuropsychological or system level. The authors will thus conclude this

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paper with a discussion of how the action of a drug at a synaptic level may be translated into the gradual erosion of the mental experience of delusions and hallucinations that occurs as part of the clinical response. This article draws heavily upon previous work by the author and colleagues (Kapur, 2003; Kapur and Remington, 2001a,b). In the interest of the synthetic effort of this review, the reader will be referred to previously published work for a more detailed discussion as well as primary references.

2. History In the early 1950s no one was looking for an antipsychotic drug. At that time psychological theories of schizophrenia were prominent, major biological theories were restricted to abnormal metabolism in the brain, and the idea of a drug acting at a receptor (itself not then widely accepted) was quite alien (Frankenburg, 1994; Healy, 2002). Rhone-Poulenc, a leading pharmaceutical maker of anti-infectious agents in the 1950s, had a program dedicated to the discovery of antihistamine drugs with the goal of improving the perioperative management of surgical patients. With antihistamines like promazine and promethazine already available, the effort was on the way to add substitutions to obtain products with superior efficacy (Healy, 2002). It was in this context that Charpentier synthesized chlorpromazine in 1950, a drug that was later tested by Simone Courvosier in animal tests of conditioned avoidance where it was noted to induce a unique state of indifference (Courvoisier, 1956; Healy, 2002). This led to its use as part of a ‘‘lytic cocktail’’ that was being used by prominent surgeon–anesthetists like Henri Laborit in their surgical efforts (Laborit and Huguenard, 1951). Laborit then brought this to the attention of psychiatric colleague Pierre Hamon at Val de Grace Military Hospital in Paris, who in turn reported the first human administration of chlorpromazine to Bernard P, a patient suffering from a manic state of agitation, which subsequently improved with the administration of chlorpromazine as part of a drug cocktail that also included barbiturates and sedatives (Frankenburg, 1994; Hamon et al., 1952; Healy, 2002). It was about this time that Delay at St. Anne in Paris became interested in chlorpromazine and used it in a large number of patients in a systematic fashion, leading to the pivotal report of the discovery of the antipsychotic actions of RP 4560 (Delay et al., 1952). However, for a variety of sociopolitical reasons well documented elsewhere (Healy, 2002), chlorpromazine did not have much impact in the United States (where it was introduced as an antiemetic and only used ‘‘off label’’ in psychotic disorders). In the 1950s, the important new drug for the treatment of psychosis in North America was reserpine, a drug that had been used for centuries as part of the Ayurvedic system of treatment for several psychiatric and nonpsychiatric treatments (Healy 2002). Systematic studies were then completed by Kline

(1955) and Hollister et al. (1955) that documented the efficacy of reserpine in patients suffering from a variety of serious psychiatric disorders. Hence, in the early 1950s, chlorpromazine and reserpine were simultaneously introduced as a treatment for psychosis in Europe and North America, respectively, and both were actively researched during this decade (Curzon 1990; Healy 2002). However, they were neither regarded as having specific efficacy in psychosis, nor restricted to the treatment of schizophrenia, assuming instead a broad indication as ‘‘tranquilizers’’ for several nervous psychiatric ailments. Lasting theories regarding the mechanism of action of antipsychotics were introduced to the field a decade after their clinical efficacy was established. Carlsson and Lindquist (1963) studied the effects of haloperidol and chlorpromazine and showed that they increased the turnover of monoamines as reflected by increased levels of their metabolites. Based on these observations, they suggested that these drugs may block monoamine receptors resulting in an increase in monamine metabolites as a compensatory effect. This led Van Rossum (1967) to postulate that antipsychotics might actually work via their action on dopamine receptors, although it was not until the work by Seeman and colleagues (and parallel findings by Synder and colleagues) that these receptors were actually identified and firmly linked to antipsychotic response (Creese et al., 1976; Seeman and Lee., 1975; Seeman et al., 1975, 1976). ‘‘Atypical’’ antipsychotics are often referred to as ‘‘novel’’ antipsychotics, although even the prototypical atypical antipsychotic clozapine is owed to this same era as ‘‘neuroleptics.’’ In 1958, Schmutz and colleagues (Schmutz and Eichenberger, 1982) at the Wander Pharmaceutical synthesized a series of dibenzazepine tricyclic compounds, clozapine being just one of them. These new compounds were effective in some of the animal models of antipsychotic action (such as blockade of amphetamine and apomorphine induced climbing). However, in contrast to haloperidol and chlorpromazine, they were not effective in other related models (amphetamine and apomorphine induced stereotypy). Prominent psychiatrists of the day (including Delay) who used clozapine in psychotic patients were either unimpressed by its efficacy or daunted by its serious side effects (Healy, 2002; Hippius, 1989). Clozapine may have died as an antipsychotic at that point were it not for the continued interest of prominent European psychiatrists in its unique ability to provide an antipsychotic effect without neuroleptic activity. It was this atypical profile of clozapine that led to its pharmacotherapeutic survival, long before it was ‘‘rediscovered’’ through the results of the famous ‘‘Study 30’’ by Kane et al. (1988). This in turn led to its full-scale introduction in North America, bringing in its wake the new series of atypical antipsychotics available today. This historical review points to two important lessons. The discovery of antipsychotics (including atypical antipsychotics) was serendipitous and the subsequent theories on their mechanism of action have largely capitalized on

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these early discoveries. Secondly, in the first 10 years of the modern antipsychotic era, reserpine (a drug acting presynaptically to modulate dopamine release) had as much sway as chlorpromazine, at least in North America. However, the subsequent 40 years of pharmacotherapy and drug development have focused largely on receptor blockade rather than release modulation, a trend that may well change in the future. Moreover, all current antipsychotic drugs derive from a direct lineage, either in terms of chemical structure or of receptor theory to the qualities embedded in chlorpromazine or clozapine—the first typical and atypical antipsychotics. Thus, after 50 years of research, the newer drugs depart from the earlier discoveries in a quantitative rather than categorical fashion, and neuroscience-led pharmaceutical endeavors to make antipsychotics with categorically different pharmacological profiles have not as yet been successful.

3. Atypical antipsychotics—how we got here and what is atypical about them The term ‘‘antipsychotic’’ itself is a relatively recent concept given the 50 year history of this class of drugs. True to their serendipitous origins, the name antipsychotic arose a decade or two after the drugs were invented. Laborit, the surgeon–anesthetist using these drugs as agents in his lytic-cocktail saw them as ‘‘ganglioplegic’’ or ‘‘neuroplegic,’’ essentially neuron-paralyzing agents (see Healy, 2002), and in keeping with their advantage in producing a state of indifference toward the surgical state labeled them ‘‘ataractics’’ (from the Greek ataraxia, a state of being without agitation) (Healy, 2002). It eventually became clear that the drugs produced a calmness quite separate from their sedative properties and resulted in motor side effects resembling those of patients with Parkinson’s disease. This led Delay et al. (1952) to suggest that a single underlying property of the drug produced both the psychomotor indifference (which led to clinical improvement) as well as the motor impairment (the main side effect). Thus, they introduced the term neuroleptic—or the ability to seize the neuron (as opposed to paralyzing it)—to describe these drugs (Courvoisier, 1956; Delay et al., 1952; Healy, 2002). At the same time in North America, it was reserpine that had just proven itself efficacious in randomized controlled trials. Reserpine and chlorpromazine were seen more as major drugs restricted for use in inpatient settings, in contrast to the ‘‘milder’’ drugs (such as the newly introduced ‘‘Miltown’’), which were considered more efficacious in outpatient settings (Healy, 2002). This led to the epithet ‘‘major tranquilizers’’ for the former, and the niche of ‘‘minor tranquilizers’’ for the latter. The trend to call them antipsychotics is historically more recent, with increasing number of references to this term in the late 1960s. Sometime later the term atypical took hold, when it was observed that clozapine was an effective antipsychotic without caus-

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ing catalepsy in animal models or extrapyramidal side effects (EPS) in patients (King and Voruganti, 2002). What does the term atypical antipsychotic mean today? The term atypical has been used too promiscuously for it to have a very rigid scientific meaning. Yet, the remarkable frequency of its use (including as a title to this issue) and the failure of more scientifically reliable terms to replace it suggests that the term conveys a valuable meaning. At least in the clinical circles most would agree that clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone and now aripiprazole and amisulpride are atypical—even though many of those agreeing to the above list may disagree on their criteria of definition. So, what unites these drugs? Compared to older antipsychotic drugs, atypical antipsychotics show fewer EPS and require less concomitant anticholinergic use, even when controlling for high doses of haloperidol that have conventionally been used in such studies (Geddes et al., 2000). The second most commonly shared feature is that most of the newer atypical antipsychotics show either no, or only transient, prolactin elevation. The two notable exceptions in this regard are risperidone and amisulpride, and it is now understood that this exception may largely be attributed to these drugs having a higher peripheral/central distribution ratio, thereby leading to excessive dopamine blockade in the pituitary that lies outside of the blood – brain barrier (Kapur, 2003). Several other issues have been raised as central to atypical antipsychotic activity, notable amongst them being effects on negative symptoms, mood and affective symptoms as well as efficacy in ‘‘refractory’’ schizophrenia. With regard to negative symptoms there are reasonable data that atypical antipsychotics, as a class, show greater improvement in negative symptoms as compared to high-dose typical antipsychotics, although it remains unclear whether this is just a reflection of lower EPS (a more primary property) or a primary efficacy against negative symptoms (Leucht et al., 2002). While there is some suggestion of superior efficacy against positive and affective symptoms, it remains unclear whether this improvement can be sustained beyond the confounds of selection bias and dose inequities (Geddes et al., 2000; Leucht et al., 2002). Finally, clozapine’s superior efficacy in patients who have not responded to adequate doses to two or three other antipsychotics, be they typical or atypical, is another quality sometimes corralled under the definition of atypicality. However, some recent trials have found a diminishing effect size of the clozapine advantage, and some fail to find it at all (Geddes et al., 2000; Remington and Kapur, 2000; Tuunainen et al., 2000; Worrel et al., 2000).

4. Atypical antipsychotics—a central role for dopamine D2 receptors What accounts for atypical antipsychotic activity at a molecular and system level? The search for the mechanism

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of atypicality is made complex by the fact that the ‘‘prototype’’ atypical antipsychotic, clozapine, shows effects at multiple receptors (i.e., dopamine D1, D4, histamine H1, serotonin 5-HT2, muscarinic M1) in addition to its effects on the dopamine D2 receptor (Schotte et al., 1996). This in turn has led to several competing ideas about what makes clozapine atypical, with two principal conceptually contrasting themes. According to one theme, the actions of atypicals on non-D2 receptors are the key to atypicality, although the accounts differ on which precise non-D2 receptor is critical. The actions at the serotonin 5-HT2 receptor (Meltzer, 1989; Meltzer et al., 1989a,b), the serotonin 5-HT1A receptor as a partial agonist (Meltzer, 1999), the dopamine D1 (Miller et al., 1990), the dopamine D3 (Schwartz et al., 2000) or the dopamine D4 receptor (Seeman et al., 1997; Van Tol et al., 1991) have all been implicated. A contrasting theme (defended here) suggests that an optimal modulation of the D2 receptor is a necessary and sufficient condition to obtain atypical antipsychotic activity (Kapur and Seeman, 2001; Seeman et al., 1997). The most widely accepted basis for atypicality has been the serotonin – dopamine hypothesis, according to which a certain ratio of serotonin 5-HT2 to dopamine D2 affinity is the most critical mechanism behind the atypical antipsychotic action of several of the new atypical antipsychotics (Meltzer, 1999; Meltzer et al., 1989a,b). However, there are several arguments against this hypothesis. First, there has been no direct demonstration that the addition of 5-HT2 antagonism to ongoing treatment through D2 blockade leads to an atypical profile of antipsychotic effects. Second, several typical antipsychotics actually have very high affinity at the 5-HT2 receptor. Conversely, many of the atypical antipsychotics when used in high doses seem to lose their atypical characteristics, suggesting that high affinity for 5HT2 may not be a sufficient explanation for atypicality (Kapur et al., 1995; Kapur et al., 1999). Third, drugs that have a very high affinity for the 5-HT2 receptor alone, without any notable affinity for the D2 receptor e.g., ritanserin, MDL 100,907, have failed to show a reliable antipsychotic effect, typical or atypical. Furthermore, the relative degree of atypicality of the antipsychotics (i.e., their freedom from EPS) does not follow the order of their 5-HT2/ D2 ratios. For example, by most accounts the order of freedom from EPS is as follows: quetiapine > olanzapine>risperidone, whereas their 5-HT2/D2 ratios are in exactly the opposite order, i.e., risperidone [21]>olanzapine [8.9]>quetiapine [2.6] (Schotte et al., 1996). Thus, while most of the current atypical antipsychotics do have a higher affinity for 5-HT2 vs. D2 receptors, and data from animal studies and basic neurobiology do provide evidence that manipulation of the 5-HT2A system may modulate the effects of the D2 system (13, 14), the sum of evidence suggests that the appropriate action at the 5-HT2 receptor, by itself, is neither necessary nor sufficient for atypical antipsychotic activity. An alternative account suggests that typical as well as atypical antipsychotics represent a continuum of dopamine

D2 receptor modulation. It is proposed that a faster dissociation rate (koff) from the dopamine D2 receptor, which results in a lower overall affinity for the dopamine D2 receptor (Kapur and Seeman, 2001), is the major contributor to atypical antipsychotic activity. This proposal reconciles one of the central findings of the 5-HT2/D2 account, i.e., a lower affinity at the dopamine D2 receptors being the single biggest discriminator of typical/atypical antipsychotics even in the face of a multireceptor profile (Meltzer et al., 1989a,b). In fact, a lower affinity at the dopamine D2 receptors is a far better predictor of atypicality than the 5HT2 affinity of an atypical antipsychotic (Kapur and Seeman, 2001). The ‘‘fast-off’’ proposal is also consistent with the suggestion by others (Hartvig et al., 1986; Seeman and Tallerico, 1998) that atypicals are distinguished by their ‘‘loose’’ binding to the dopamine D2 receptor. How drugs with lower affinity/faster dissociation might lead to atypicality is not clear. Drugs with lower affinity and faster dissociation are often given at comparably higher doses. Thus, faster dissociation by itself does not mean a lesser effect on the dopamine D2 system. One could, in principle, give a proportionally higher dose of a fast-koff drug and obtain high levels of occupancy. However, because drugs with a faster dissociation are likely to be more responsive to physiological phasic bursts of dopamine transmission, they should attenuate dopamine transmission with lesser distortion of physiological signaling (Kapur and Seeman, 2001). It has also been proposed (see below) that atypical antipsychotics may show a higher degree of occupancy in the extrastriatal regions (Bigliani et al., 2000; Xiberas et al., 2001). Whereas this claim itself is not without controversy, it is compatible with the idea that atypical antipsychotics, by virtue of their greater sensitivity to endogenous dopamine, would be more sensitive to competition in the striatum while acting as effective blockers of dopamine transmission in the extrastriatal regions. Thus, it is proposed that through appropriate modulation of the dopamine D2 receptor itself it is possible to get preferential modulation of the mesolimbic vs. striatal dopamine system, an empirical observation in animal models that best predicts atypical antipsychotic effect in patients.

5. Is appropriate modulation of dopamine D2 receptors sufficient for atypical antipsychotic activity? Once again, this question is complicated by the fact that most of the newer atypical antipsychotics act at multiple receptors. One of the most interesting comparative analyses is provided by a meta-analysis of randomized controlled trials that compared the specific dopamine D2/3 antagonist amisulpiride to multireceptorial atypicals: clozapine, risperidone, olanzapine and quetiapine (Lewis, 2002). The results of this meta-analysis demonstrate that despite being a selective D2/3 antagonist, amisulpride shows as much atypicality as the 5-HT2/D2 drugs (Leucht et al., 2002). These

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results are consistent with more recent double-blind studies comparing amisulpride to risperidone (Peuskens et al., 1999) and olanzapine (Martin et al., 2002). The main conclusion that one can draw from these studies is that action at the dopamine D2/3 receptors is, by itself, sufficient to provide the atypical antipsychotic activity we now associate with these novel antipsychotic drugs. If this is the case, then it raises an important question that will be addressed in the next section, that is, do all antipsychotics block the dopamine D2 receptor in a similar fashion?

6. Antipsychotics and dopamine D2 receptor occupancy—similarities and differences The advent of neuroimaging has made it possible to investigate the receptor occupancy of antipsychotics in medicated patients. The usefulness of this was first demonstrated by Farde et al. (1988) who showed that most antipsychotics, with the exception of clozapine, showed high (70% and above) D2 occupancy at usual clinical doses. Positron emission tomography (PET) studies have suggested the presence of a ‘‘therapeutic window’’ of dopamine D2 receptor occupancy for most antipsychotics, with 60 – 65% receptor blockade being the optimal level for antipsychotic response and occupancies greater than 80% being associated with increased incidence of EPS (Farde et al., 1992; Kapur et al., 2000a; Nordstrom et al., 1993). Using the same methodology, risperidone has also been shown to be clinically effective at a level of D2 receptor occupancy previously seen with typical antipsychotics, i.e., at doses of 2 mg it exhibits 60% or greater D2 occupancy (Kapur et al., 1999). Furthermore, at this low dose the serotonin 5-HT2 receptors are already saturated (Farde et al., 1995; Kapur et al., 1999), suggesting that occupancy of 5-HT2 receptors is not sufficient to produce an antipsychotic response. Olanzapine also shows a preferential blockade of serotonin 5HT2 receptors as compared to the dopamine D2 receptors (Kapur et al., 1998; Nyberg et al., 1997), and like risperidone shows high occupancy of serotonin 5-HT2 receptors even at subtherapeutic doses. Clozapine, the protopical atypical antipsychotic has now been extensively investigated using PET (Farde and Nordstrom, 1992; Kapur et al., 1999; Nordstrom et al., 1995b). Similar to risperidone and olanzapine, it shows very high occupancy of the serotonin 5-HT2 receptors even at very low (subtherapeutic) doses (50 mg/day) (Kapur et al., 1999). On the other hand, clozapine’s antipsychotic efficacy, at least in refractory patients, is best seen with plasma levels of 300 to 400 ng/ml, which are associated with a D2 receptor occupancy in the range of 50– 60% (Kapur et al., 1999; Nordstrom et al., 1995b). While controlled comparative studies are not available, all the published data suggest that clozapine’s D2 occupancy, at least at the time points measured, is lower than that of typical antipsychotics as well as risperidone and olanzapine. Moreover, it is consis-

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tently lower than the threshold required for EPS or prolactin elevation. This low level of D2 receptor occupancy, therefore, is the simplest and perhaps only explanation required to explain why clozapine does not give rise to EPS and sustained prolactin elevation (Farde and Nordstrom, 1992; Kapur et al., 1999). However, while clozapine’s effects on D2 receptors may indeed account for its clinical atypicality (i.e., absence of EPS or sustained prolactin elevation, fewer secondary negative symptoms and, perhaps, decreased cognitive impairment), it does not necessarily explain its superior efficacy in refractory patients. Quetiapine, like clozapine, risperidone, and olanzapine, also exhibits higher 5-HT2 than D2 receptor occupancy at all clinical doses studied (Gefvert et al., 1998; Kapur et al., 2000b). However, even at doses of 450 –600 mg/day its D2 occupancy is < 30% 12 h after the last dose. However, recent studies examining the time course of D2 receptor occupancy with quetiapine have demonstrated a higher D2 occupancy (45 – 60%) within 2– 3 h of its administration, subsequently declining rather rapidly as predicted by its fast pharmacokinetics during the interdose interval (Gefvert et al., 1998; Kapur et al., 2000b). Like clozapine, its low level of D2 occupancy may account for its very low risk of EPS and prolactin elevation. This may also explain why doses of 150 – 300 mg/day show questionable efficacy (Small et al., 1997) since the dose of quetiapine required to reach a peak occupancy of 60% would be 600– 800 mg/day or above. Amisulpride, unlike the other atypicals reviewed here, does not have any affinity for the serotonin 5-HT2 receptors (Trichard et al., 1998). Doses of amisulpride between 600 and 900 mg/day achieve 70 – 80% D2 occupancy, while doses >1100 mg/day result in >85% D2 occupancy resulting in dose-dependent EPS at these higher levels (Martinot et al., 1996). Amisulpride shows an optimal balance between efficacy and diminished EPS risk in the 400 – 800 mg/day range (Freeman, 1997), as would be predicted from its D2 occupancy. Aripiprazole (recently released in the United States) is primarily a partial agonist at the dopamine D2 receptors, showing highest affinity for the dopamine D2 receptor and a lower affinity for the serotonin 5-HT2 or 5-HT1A receptors. PET imaging data from normal volunteers show that aripiprazole, at clinically relevant doses, produces very high levels of D2 occupancy with virtual saturation of the dopamine D2 receptors (Yokoi et al., 2002). In contrast to previously discussed antipsychotics, this is not accompanied by either EPS or prolactin elevation, consistent with its action as a partial agonist at the D2 receptor (Burris et al., 2002).

7. Differential effects at the striatal vs. extrastriatal dopamine D2 receptors Most of the studies cited above focused on ‘‘striatal’’ dopamine D2 receptor blockade. However, there is increasing interest in examining the effects of antipsychotics in the

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extrastriatal regions (mainly the thalamus, frontal and temporal cortex). Some reports suggest that atypical antipsychotics (clozapine, olanzapine, sertindole, risperidone and amisulpride) show a preferential blockade of the cortical dopamine D2 receptors compared with striatal dopamine D2 receptors. These results contrast with haloperidol, which shows equal D2 receptor occupancy in these regions (Bigliani et al., 2000; Xiberas et al., 2001). These reports have been questioned on methodological grounds (Olsson and Farde, 2001), and there are reports to the contrary (Talvik et al., 2001). However, what is of interest is that atypical antipsychotics, regardless of whether they are multireceptorial or D2 specific, share this property. The precise molecular basis for this difference, if indeed this striatal – extrastriatal difference were to be shown to be a reliable finding, is not entirely clear. However, it has been suggested that differences in the way that the different antipsychotics interact with the dopamine D2 receptor (i.e., different affinity or koff) may be relevant to how these differential striatal vs. extrastriatal effects may influence antipsychotic atypicality (Kapur and Seeman, 2002).

8. Why are antipsychotics anti-‘‘psychotic’’? Most theories regarding antipsychotics, some of which are touched upon above, are largely biological theories. However, psychosis is an experiential phenomenon, a subjective ‘‘mind’’ experience. How does one bridge the biology of psychosis, the phenomenology of its experience, and the pharmacology of its treatment? We propose that the concept of ‘‘motivational salience’’ provides an important link between these different empirical realities of schizophrenia (Kapur, 2003). Over the past few decades, a large body of evidence has accumulated linking excessive dopamine transmission to psychosis. Psychostimulant agents that trigger the release of dopamine are associated with de novo psychosis or worsening of preexisting psychosis. Postmortem data also show abnormalities in dopaminergic indices in schizophrenia, although the interpretation of these data was always confounded by drug effects (Angrist and Gershon, 1970; Angrist et al., 1974, 1980; Davis et al., 1991; Harris and Batki, 2000; Seeman, 1987). More direct evidence emerges from neuroimaging studies (Laruelle and AbiDargham, 1999; Seeman and Kapur, 2000; Soares and Innis, 1999)), which show a increased dopamine synthesis (Hietala et al., 1995; Lindstrom et al., 1999; Meyer-Lindenberg et al., 2002; Reith et al., 1994), an exaggerated release of dopamine (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996), higher than normal levels of dopamine at baseline when psychotic (Abi-Dargham et al., 2000; Gjedde and Wong, 2001) and some conflicting suggestions regarding an increase in receptor number (Andreasen et al., 1988; Farde et al., 1990; Nordstrom et al., 1995a; Wong et al., 1986, 1997). How can one link dopamine, psychosis and antipsychotic action in a manner that bridges the biological

to the experiential? To address this issue, we will present a synopsis of a hypothesis of motivational salience, which has been reviewed in detail elsewhere (Kapur, 2003). There is near universal agreement for a central role of dopamine in ‘‘reward’’ and ‘‘motivation,’’ although exactly what is meant by these terms is a matter of debate. Berridge and Robinson (1998) propose that one of the functional roles of dopamine is to mediate the conversion of an external stimulus from a neutral or ‘‘cold bit’’ of sensory information into an ‘‘attractive’’ or ‘‘aversive’’ entity (Berridge, 1999; Berridge and Robinson, 1998). In particular, the mesolimbic dopamine system is seen as a critical component in this ‘‘attribution of salience,’’ a process whereby events and thoughts come to one’s attention, drive action and influence goal-directed behaviour as a consequence of their association with reward or punishment (Berridge, 1999; Berridge and Robinson, 1998). Under normal circumstances, it is the stimulus-driven release of dopamine that mediates the acquisition and expression of appropriate motivational salience in response to one’s experiences and predispositions (Berridge, 1999; Berridge and Robinson, 1998; Heinz, 1999; Shizgal, 1997). Dopamine mediates the process of motivational salience; it does not create this process. It is proposed that in psychosis the dysregulated dopamine transmission leads to a stimulusinappropriate release of dopamine. This neurochemical aberration usurps the normal process of salience attribution and leads to aberrant assignment of salience to external objects and internal representations. Thus, dopamine, which under normal conditions is a mediator of contextually relevant salience, in the psychotic state becomes a creator of salience, albeit an aberrant one (Kapur, 2003). In this framework, delusions are ‘‘top-down’’ cognitive explanations that the individual imposes upon these aberrant salience experiences in an effort to make sense of them. Because delusions are constructed by the individual, they are imbued with the psychodynamic themes relevant to the individual and are embedded in the cultural context of the individual. This explains how the same neurochemical dysregulation leads to variable phenomenological expression: a patient in Africa struggling to make sense of aberrant salience experiences is much more likely to accord them to the evil ministrations of a Shaman, whereas the one living in Toronto is more likely to see them as the maneuverings of the Royal Canadian Mounted Police (Kapur, 2003). Within the same framework, hallucinations arise from a conceptually similar but a more direct process: the abnormal salience of internal representations of percepts and memories leads to the subjective experience of these internal representations in a manner that is vivid and real, such that one is led to mistake this internal (virtual) experience with that of an external reality. How do antipsychotics reverse this process? It is proposed that antipsychotics are efficacious in psychosis because, by their biological actions (which involve dopamine at some level), they ‘‘dampen salience’’ of the subjective

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experience of delusions and hallucinations. In this scheme, antipsychotics only provide a platform of dampened salience, and the process of symptomatic improvement requires further psychological and cognitive resolution. Antipsychotics do not change thoughts or ideas primarily, but provide a neurochemical milieu wherein new aberrant salience experiences are less likely to form and previously acquired aberrant salience experiences are more likely to extinguish (Clody and Carlton, 1980; Miller, 1987, 1989). Indeed, this is consistent with how patients experience their symptomatic improvement with antipsychotic treatment. Patients do not immediately abandon the psychotic idea or percept, but report that the idea or percept ‘‘doesn’t bother me as much’’ (Elkes and Elkesm, 1954; Winkelman, 1954). While some patients do actually achieve complete resolution of their delusions and hallucinations with antipsychotic treatment, for many patients a dampening of symptoms is as good a resolution as antipsychotics can provide. At the same time, because the antipsychotic cannot limit itself only to dampening the salience of symptoms, some normal-life saliences may also get dampened, perhaps leading to what is often called neuroleptic-induced dysphoria or drug-induced negative/depressive symptoms.

9. Conclusions, qualifications and implications The preceding sections focused on the putative role of dopamine and D2 receptors as a common factor in antipsychotic drug action. This does not imply that other receptors and neurotransmitter systems may not be involved in the pathophysiology of psychosis and antipsychotic drug action. Various candidates have been proposed: serotonin 5-HT2 receptors (Meltzer et al., 1989a), D4 (Van Tol et al., 1991), glutamate (Olney and Farber, 1994, 1995), alpha adrenergic receptors (Svensson et al., 1995) and others (Gerlach and Casey, 1994) (some of these are discussed elsewhere in the series). Action at these other receptors has been proposed to enhance efficacy on the psychotic and nonpsychotic dimensions as well as reduce side effects. One must bear in mind, however, that amisulpride’s pharmacology suggests that it is possible to achieve contemporary atypical antipsychotic activity without action at any of these other receptors. Moreover, to date, drugs targeting any of these receptors either by themselves or in combination have not shown antipsychotic activity unless accompanied by at least some element of dopamine D2 receptor blockade. Thus, action at dopamine D2 receptors remains a necessary and putatively sufficient condition to achieve contemporary levels of atypical antipsychotic effects. However, this focus on dopamine D2 receptors also underscores the relative poverty of therapeutic options. Several unmet therapeutic needs remain: First, in a large majority of patients, the improvement of psychosis is incomplete. Although clozapine is often seen as an option for these patients, the additional efficacy of clozapine is modest at

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best. Second, even newer antipsychotics have limited efficacy against the negative/deficit dimensions of schizophrenia. Thus, one is often left with a patient whose ‘‘psychosis’’ (i.e., positive symptoms) is improved, but who continues to exhibit functional impairment. Third, the heightened therapeutic optimism ushered by the newer antipsychotics has drawn our attention to a major hurdle in restoring function, that is, the primary cognitive dysfunction in schizophrenia. Currently available antipsychotics address this deficit only partially and perhaps only secondarily. Fourth, while the motor side effects are much diminished by the newer antipsychotics, new side effects have come to the forefront: weight gain, lipid dysmetabolism and insulin resistance have become new challenges with some of the agents. It is likely that the next generation of treatments will have to move beyond reliance on a single drug as the sole treatment for the multidimensional disorder of schizophrenia. There is little debate that optimal treatment of schizophrenia will require action at more than just the dopamine system. This does not mean that all the different targets need to be bundled in one pill. In fact, our current approach of multireceptor atypicals can be viewed as a kind of one-sizefits-all polypharmacy-in-a-pill. In most other branches in medicine, optimization of therapy of disorders involving more than a single physiological dysfunction (as is often the case in cancer, hypertension, arthritis) is usually achieved by different preparations each with its unique pharmacology and indications. Thus, one can look forward to a time where there will be different therapeutic strategies, each uniquely targeting a different dimension of schizophrenia, be it a positive, negative, cognitive or affective manifestation of the same syndrome. It will then be the physician’s job to flexibly target these signs and symptoms, and to titrate these strategies to match the dimensionality of the illness and its diverse manifestations in each patient.

Acknowledgements The authors would like to thank Drs. Robert Zipursky, Gary Remington, Phil Seeman and Paul Fletcher for the intellectual environment in which these thoughts were conceived and nurtured—and for the many ongoing conversations about the true nature and basis of antipsychotic action. This work is supported by a Canada Research Chair in Schizophrenia and Therapeutic Neuroscience, as well as operating grants from the CIHR (Canada) and Stanley Foundation (USA).

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