Antipsychotic efficacy: Relationship to optimal D2-receptor occupancy

European Psychiatry 22 (2007) 267e275 http://france.elsevier.com/direct/EURPSY/

Review

Antipsychotic efficacy: Relationship to optimal D2-receptor occupancy Luca Pani a,b,*, Luigi Pira a, Giorgio Marchese a b

a PharmaNess S.c.a.r.l, Technological Park - Sardegna Ricerche, Pula (CA), Italy C.N.R., Institute of Biomedical Technology Sect. Cagliari, c/o Technological Park - Sardegna Ricerche, Pula (CA), Italy

Received 3 August 2006; received in revised form 19 January 2007; accepted 12 February 2007 Available online 6 April 2007

Abstract Clinically important differences exist between antipsychotic agents and formulations in terms of safety and tolerability. Features of the biochemical interaction between the antipsychotic and the D2-receptor may underlie these differences. This article reviews current information on the relationship between antipsychotic receptor occupancy and clinical response. A literature search was performed using the keywords ‘antipsychotic or neuroleptic’, ‘receptor’ and ‘occupancy’ and ‘dopamine’ and ‘D2’ supplemented by the authors’ knowledge of the literature. Imaging and clinical data have generally supported the hypotheses that optimal D2-receptor occupancy in the striatum lies in a ‘therapeutic window’ between w65 and w80%, however, pharmacokinetic and pharmacodynamic properties of a drug should also be taken into account to fully evaluate its therapeutic effects. Additional research, perhaps in preclinical models, is needed to establish D2-receptor occupancy in various regions of the brain and the optimal duration of D2-receptor blockade in order to maximise efficacy and tolerability profiles of atypical antipsychotics and thereby improve treatment outcomes for patients with schizophrenia. Ó 2007 Elsevier Masson SAS. All rights reserved. Keywords: Antipsychotic; Atypical; Dopamine; Receptor; Occupancy; Extrapyramidal symptoms

1. Introduction An increasing body of evidence from positron emission tomography (PET) studies suggests that there are relationships between the clinical response and side effects observed with antipsychotic therapy, and factors such as antipsychotic dose and receptor occupancy in different regions of the brain. In particular, antipsychotic occupancy of dopamine D2-receptors has been the focus of extensive research. Blockade of cortical and limbic dopamine D2-receptors is thought to mediate both clinical response to antipsychotics and the occurrence of adverse events. D2-receptor-related adverse events are mediated

* Corresponding author. PharmaNess S.c.a.r.l, and C.N.R., Institute of Biomedical Technology, Sect. Cagliari c/o PharmaNess S.c.a r.l., Building 5, Technological Park - Sardegna Ricerche, 09010 Pula (Cagliari), Italy. Tel.: þ39 070 924 2029; fax: þ39 070 924 2206. E-mail addresses: [email protected] (L. Pani), luigi.pira@ pharmaness.it (L. Pira), [email protected] (G. Marchese). 0924-9338/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2007.02.005

via blockade of striatal and tuberoinfundibular D2-receptors, which are associated with extrapyramidal symptoms (EPS) [69] and prolactin elevation [9], respectively. Side effects and poor clinical response are of concern since they can lead to discontinuation of study medication, subsequent patient relapse and, thus, contribute to suboptimal treatment outcomes. Several systematic reviews concur in suggesting that the newer atypical antipsychotics achieve comparable efficacy accompanied by a lower incidence of EPS [11,56] when compared with conventional agents. Indeed, data from randomized clinical trials of aripiprazole [34,41], ziprasidone [7,31], risperidone [48], quetiapine [28] and olanzapine [75] have shown these agents provide comparable or superior efficacy and improved tolerability profiles compared with haloperidol. It is noteworthy, however, that some of the atypical agents are associated with increased incidences of metabolic side effects, including weight gain and dyslipidemia [1]. The recent CATIE study demonstrated that the conventional agent perphenazine,

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had similar discontinuation rates as the atypical agents olanzapine, quetiapine, risperidone and ziprasidone [46] and, as such, further studies are needed to fully evaluate the potential advantages in terms of the efficacy and safety profile of atypical agents compared with conventional agents. Moreover, several studies have reported clinical benefits of reduced relapse after switching from orally administered antipsychotic to longacting formulations [14,59]. Although clinical efficacy and incidence of side effects might differ between oral immediate-release and long-acting formulations of conventional and atypical antipsychotics, these therapies share D2-receptor blockade as the primary mechanism of antipsychotic action. It is, therefore, possible that several aspects might combine in determining the final pharmacological effects produced by the D2-receptor blockade. Among them, three features of the biochemical interaction between the antipsychotic agent and the D2-receptor might be particularly relevant for the clinical outcome: (1) the level (thresholds) of D2-receptor occupancy; (2) the dissociation (affinity) of the drug to the D2-receptor; and (3) the availability of the drug to the receptor over time. Studies have demonstrated that the atypical antipsychotics generally have a much lower affinity for D2-receptors than the older, conventional antipsychotic agents [63e65]. Moreover, several authors have highlighted that D2-receptor occupancy and dissociation rates are an important consideration, although few studies have really addressed the question of optimal duration of D2-receptor occupancy. Finally, the recent introduction of a long-acting atypical antipsychotic indicates that clinical benefits, in terms of relapse prevention and therapy outcome, might occur when this pharmacological strategy is adopted. Thus, although it can be postulated that a favourable equilibrium exists between D2-receptor occupancy, dissociation of the drug from the D2-receptor and availability of the drug to the receptor, further work is required to study these pharmacological aspects in detail, with regard to the potential clinical benefit and impact on the development of new antipsychotic agents. This article will examine the available information with regard to the relationship between antipsychotic receptor occupancy and clinical response and side effects. The contribution of different aspects of the antipsychoticereceptor interaction (occupancy thresholds, dissociation and availability over time) will also be reviewed. 2. Methods A literature search was performed using the keywords ‘antipsychotic or neuroleptic’, ‘receptor’ and ‘occupancy’ and ‘dopamine’ and ‘D2’. Additional articles were included based on the authors’ knowledge of the literature and after reviewing the reference lists of retrieved articles. Abstract books from recent congresses were also reviewed. 2.1. D2-receptor occupancy thresholds In light of the clinical relevance of combining optimal therapeutic efficacy with a low incidence of side effects, several

studies have investigated whether the different pharmacological effects induced by antipsychotic drugs could be related to progressively exceeding threshold limits of D2-receptor occupancy. Using basal ganglia as an index of the D2-receptor occupancy induced by antipsychotic drugs in the brain, imaging studies suggest that a D2-receptor occupancy of greater than 65% is necessary for an antipsychotic effect to be observed, regardless of the type of drug [37,61]. In addition, preclinical and human studies have shown that EPS are observed if striatal D2-receptor occupancy exceeds around 80%, as the access of endogenous dopamine to the receptors within this region is substantially reduced, leading to a relative increase in cholinergic activity that impairs motor function [12,37,68,69]. Using [11C]-raclopride PET, it has been demonstrated that patients with schizophrenia receiving therapeutic stable doses of conventional antipsychotics and experiencing EPS have an average D2-receptor occupancy within the striatum of 82%, compared with 74% in patients who did not experience EPS while receiving these agents (Table 1) [22]. These results have been confirmed using [123I]-IBZM SPECT, with the highest EPS rates observed in patients treated with haloperidol (mean D2-receptor occupancy of 85%) compared with lower mean D2-receptor occupancy of 20e74% and lower rates of EPS observed in patients treated with atypical agents including clozapine, olanzapine, risperidone and quetiapine (Table 1) [73]. A similar study with olanzapine has demonstrated that doses of 10e20 mg/day achieve mean D2-receptor occupancy of around 75%, and that increasing the dose and, therefore, the D2-receptor occupancy to >80%, produces akathisia. Furthermore, doses higher than 20 mg/ day of olanzapine were also associated with an increased likelihood of prolactin elevation (Table 1) [39]. A correlation between subjective response to antipsychotic treatment and D2-receptor occupancy has been proposed. D2-receptor occupancy of 60e70% (as measured by [123I]-IBZM SPECT) was associated with a significantly higher (i.e. more favourable) total score on the Subjective Wellbeing Under Neuroleptics Scale (SWN) [15] (Table 1). This correlation was also observed for scores on all the subscales of the SWN, and was similar for haloperidol and olanzapine [15]. These data suggest that a D2-receptor ‘occupancy window’ might exist in which a drug exerts its antipsychotic activity without inducing EPS. EPS may occur when the D2-receptor blockade involves more than 85% of the striatal D2-receptors. Although the D2-receptor ‘occupancy window’ concept is generally accepted, its applicability requires several distinctions depending on the drug and on the pharmacological effect to be considered. Low D2-receptor striatal occupancies have been reported following clozapine and quetiapine administration. These findings are based on scans taken 6 or 12e14 h [22,73] after the last oral dose and, therefore, allowances must be made given the rapid decline in clozapine and quetiapine D2-receptor occupancy within 24 h of last dose [62]. Two small studies have shown that quetiapine achieves a transient striatal D2-receptor occupation (mean 62% at peak and 14% at trough within 24 h of a once-daily dose of up to 400 mg)

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and that this correlates with improvements in psychotic symptoms and a reduction in the severity of illness [38,74]. However, there was no significant difference in peak of striatal D2-receptor occupancy between responders and nonresponders (65.9% versus 60.3%; p ¼ 0.446) and, as such, further studies are required in order to clarify the relationship between striatal D2-receptor occupation and the therapeutic efficacy of quetiapine. The transient D2-receptor occupancies observed in patients receiving clozapine [22] and quetiapine reflect the reduced EPS liability of the drugs [22,38]. However, it could be argued that only a few hours a day of adequate D2receptor occupancy might be sufficient for clinical alleviation of the psychosis [38,74], unless quetiapine and clozapine mediate their antipsychotic effects in a non-D2-dependent manner which has yet to be elucidated. Although striatal D2-receptor occupancy measurements can be reliably quantified with [11C]raclopride and PET, extrapolation of these results to other brain areas should be considered with caution. This is due to the fact that a drug’s antipsychotic activity occurs primarily as a result of D2-receptor blockade in extrastriatal brain regions [49,53]. Most of the available studies, with only a few exceptions, demonstrate that the majority of the second-generation antipsychotics bind preferentially to extrastriatal D2-receptors and, for some of these compounds, particularly clozapine, the difference between striatal and extrastriatal binding can be substantial. Several studies have investigated the striatal/cortical ratio of D2-receptor binding and have shown that the D2-receptor binding index was high in the temporal cortex for haloperidol, risperidone, clozapine, amisulpride and olanzapine (Table 1). However, in the striatum, the binding indices for the atypical antipsychotics were generally lower than those for haloperidol [77]. In a study utilizing [123I]-IBZM uptake, a mean uptake ratio of 1.10 was achieved with conventional neuroleptics (haloperidol), indicating a higher striatal D2-receptor occupancy, compared with clozapine which was associated with a mean ratio of 1.22, a ratio similar to that observed in medication-free patients [6]. In addition, the mean ratio for patients treated with conventional neuroleptics and experiencing EPS was significantly lower than in those patients not experiencing EPS (Table 1). In the study performed by Scherer et al. [58] when patients were subdivided according to the presence or absence of EPS, all patients with EPS had a striatal/frontal cortex ratio 1.2. These observations might suggest that the preferential binding of atypical antipsychotic to extrastriatal D2-receptors might account for their low EPS liability. The use of striatal occupancy to predict pharmacological effects induced by the D2-receptor blockade in other areas of the brain may also be affected by idiosyncratic pharmacokinetic properties of the antipsychotic drug. It has been demonstrated that haloperidol-induced D2-receptor occupancy of 78% is associated with EPS, while elevation of plasma prolactin concentrations occurs at D2-receptor occupancies above 72% [37]. Possible correlations between striatal D2-receptor occupancy and hyper-prolactinemia induction often lead to inconsistent results when substitute-benzamides are considered. It has been reported that raclopride induces significant

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increases in plasma prolactin concentration at D2-receptor occupancy >50% [54]. Conversely, single photon emission tomography (SPET) and [123I]-epidepride studies have suggested that, at antipsychotic doses, amisulpride-induced hyperprolactinemia is uncoupled from central D2/D3-receptor occupancy [5]. The limited ability of substituted-benzamide to cross the blood-brain barrier may produce different drug concentrations at the pituitary level when compared to those of the central regions, thus affecting possible relationships between striatal D2-receptor occupancy and hyper-prolactinemia [5]. The development of new antipsychotic agents which act as partial agonists of the D2-receptor, led to re-evaluation of the D2-receptor occupancy thresholds required for a sufficient therapeutic effect in the absence of EPS [29]. Therapeutic doses of aripiprazole (5e40 mg/day) have been demonstrated to occupy around 90% of all central D2-receptors, without producing EPS or elevating prolactin levels. This is thought to be due to its action as a partial agonist rather than an antagonist, including its w30% intrinsic activity at dopamine post-synaptic receptors [24,71,78]. It could be extrapolated that net D2receptor antagonism produced by aripiprazole concords with that produced by full antagonist antipsychotics at therapeutic dosage; however, no direct evidence to support this hypothesis is currently available. Key differences between aripiprazole and full antagonist antipsychotics may be due to the control of remaining dopaminergic activity; these may be relevant in a comprehensive evaluation of the final behavioural effect induced by antipsychotic drugs. Pre-synaptic D2-receptor blockade induced by conventional antipsychotics is known to promote dopamine outflow from dopaminergic terminals in basal ganglia and nucleus accumbens, whereas the therapeutic advantages exhibited by atypical antipsychotic could be related to preferential dopamine release induced by these drugs in the frontal cortex [49]. To date, no data are available regarding the effect of aripiprazole on striatal dopamine release, although it has been reported that the drug marginally increases dopamine outflow in the frontal cortex, but not in the nucleus accumbens [45]. The high level of aripiprazole-induced D2-receptor occupation (>90%) [78] suggests that dopaminergic functionality may be preserved predominantly by the intrinsic activity of the drug at the D2-receptor. However, further studies are required to support this proposition and to evaluate its clinical relevance. In summary, the D2 ‘occupancy window’ concept represents advances in the elucidation of the biochemical mechanisms regulating some of the pharmacological effects induced by antipsychotic drugs. However, it should be noted that striatal D2-receptor occupancy might often not represent the distinctive pharmacodynamic and pharmacokinetic properties of a drug and, as such, any generalization of data obtained for antipsychotics should be undertaken with caution. 2.2. Dissociation from the D2-receptor The ‘D2-receptor occupancy threshold’ concept provides incomplete information regarding the different EPS liability

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Table 1 Studies investigating D2-receptor occupancy thresholds Study

Study design

Studies assessing D2-receptor occupancy

Farde et al. 1992 [22]

28 patients (18 male and 10 female) with an average age of 30.5 years (range, 18 to 49 years)

D2-receptor occupancy Clozapine ¼ 38e63% Conventional ¼ 70e89% Conventional D2-receptor occupancy and EPS occurrence 82% occupancy, EPS ¼ yes 74% occupancy, EPS ¼ no Difference between groups ( p < 0.001)

All 28 drug-treated patients underwent a PET examination to determine D2-receptor occupancy

Kapur et al. 1998 [39]

D2-receptor occupancy Olanzapine 10e20 mg/day ¼ 71e80% Olanzapine 30 mg/day ¼  80% Enrolled patients went through a washout period from D2-receptor occupancy and EPS occurrence their previous neuroleptic that lasted 2e4 days, and medication Higher D2-receptor occupancy may be associated with a higher was titrated to their assigned dose likelihood of prolactin elevation and EPS Male and female patients (18e45 years) who met the DSM-IV criteria for schizophrenia

Tauscher et al. 2002 [73] 71 patients with DSM-IV diagnosis of schizophrenia, with mean age ¼ 32.1 years  9.6 (33 females and 38 males)

Clozapine ¼ 300e600 mg/day Olanzapine ¼ 10e25 mg/day Quetiapine ¼ 300e700 mg/day Risperidone ¼ 3e8 mg/day Haloperidol ¼ 5e20 mg/day

de Haan et al. 2003 [15] Patients (n ¼ 24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment

Olanzapine (7.5 mg/day) or Haloperidol (2.5 mg/day)

D2-receptor occupancy Clozapine ¼ 33%  17 Olanzapine ¼ 74%  8 Quetiapine ¼ 20%  13 Risperidone ¼ 70%  9 Haloperidol ¼ 85%  9 EPS rate Clozapine ¼ 0% Olanzapine ¼ 0% Quetiapine ¼ 0% Risperidone ¼ 64% Haloperidol ¼ 80% D2-receptor occupancy and EPS occurrence Mean D2-receptor occupancy for EPS ¼ 77%  11 compared with 62%  22 for no EPS D2-receptor occupancy and patient subjective well being 60e70% D2-receptor occupancy ¼ 193.5  28.7 <60% D2-receptor occupancy ¼ 157.8  29.1 >70% D2-receptor occupancy ¼ 140.6  10.8 D2-receptor occupancy and SWN total score Total score on SWN was significantly higher for patients with a D2-receptor occupancy of 60e70% compared with those patients with a D2-receptor occupancy <60% ( p ¼ 0.004) or >70% ( p ¼ 0.004)

Study Xiberas et al. 2001 [77]

Study design Studies assessing D2-binding index Haloperidol, risperidone, clozapine, amisulpride and olanzapine Atypical agents High (78e92) (temporal cortex) Lower (42e63) (striatum) Conventional agents (haloperidol) Temporal cortex ¼ 92 Striatum ¼ 82

Study Broich et al. 1998 [6]

Study design 44 in patients with schizophrenia (DSM-III-R) were evaluated using IBZM-SPECT Clozapine ¼ 300  238 mg

Conventional agents Haloperidol ¼ 16.1  8.1 mg Benperidol ¼ 19.3  9.9 mg Flupentixol ¼ 10.6  4.7 mg

Studies assessing uptake ratio Conventional agents ¼ 1.10  0.09 (range: 0.96e1.39), indicating a higher striatal D2-receptor occupancy Clozapine ¼ 1.22  0.14 (range: 1.04e1.42), which was not significantly different ( p < 0.001) from that observed in medication free patients Uptake ratio and EPS Conventional agents (with EPS) ¼ 1.06  0.04 (range: 0.96e1.12), Conventional agents (without EPS) ¼ 1.17  0.10 (range: 1.07e1.39) Mean ratio was significantly lower in patients treated with conventional agents and experiencing EPS than in those not experiencing EPS ( p < 0.001)

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Table 1 (continued ) Study

Study design

Studies assessing D2-receptor occupancy

Scherer et al. 1994 [58]

27 patients (mean age ¼ 39 years, range 22e59) who met the diagnostic criteria for schizophrenia according to DSM-III-R

Haloperidol ¼ 1.15  0.05 (EPS present) Haloperidol ¼ 1.23  0.05 (no EPS) Uptake ratio was significantly lower in patients treated with haloperidol, who also had EPS ( p < 0.01) Uptake ratio between atypical and conventional agents Haloperidol ¼ 1.19  0.06 Clozapine ¼ 1.46  0.05 Patients treated with haloperidol had significantly lower uptake ratio than patients treated with clozapine ( p < 0.001) When patients are subdivided according to the presence or absence of EPS, all patients with EPS were below a threshold of striatal/frontal cortex ratio of 1.2

Mean daily dose: Haloperidol ¼ 5e21 mg Clozapine ¼ 125e400 mg

PET ¼ positron emission tomography; EPS ¼ extrapyramidal symptoms; DSM ¼ Diagnostic and Statistical Manual of Mental Disorders; SWN ¼ Subjective Wellbeing Under Neuroleptics Scale.

displayed by antipsychotic drugs. Atypical antipsychotics are known to have a lower propensity to induce EPS when compared to conventional antipsychotics, despite many of these drugs sharing comparable ‘occupancy thresholds’. Therefore, the binding interaction characteristics between antipsychotic drugs and D2-receptor should also be considered. In vitro studies have demonstrated that the binding kinetics of antipsychotics at the D2-receptor differs widely between individual drugs. The binding affinities of antipsychotics relative to endogenous dopamine vary considerably. Drugs such as clozapine, quetiapine and olanzapine bind more loosely to D2receptors than dopamine, whereas haloperidol and risperidone bind to these receptors more tightly [66,69]. It has been suggested that antipsychotics with low binding affinity and fast dissociation rates, such as clozapine and quetiapine, will be more responsive to endogenous changes in dopamine than those which bind more tightly and dissociate from the receptor more slowly [36]. In normal physiological functioning, baseline dopamine levels are interspersed with task- or stress-induced several-fold increases in dopamine that last from seconds to minutes. Slowly dissociating antipsychotics such as haloperidol are not significantly influenced by these phasic bursts of dopamine and, therefore, alter or even extinguish physiological dopamine transmission. This sequelae differs from that observed with rapidly dissociating antipsychotics, whereby pulses of dopamine are accommodated to a much greater extent, and physiological dopamine transmission is competitively attenuated but not abolished [36]. The ability of the antipsychotics to compete with endogenous dopamine may play a role in determining their propensity to induce EPS. Endogenous dopamine levels in the limbic system are only around 10% of those in the striatum; as such, endogenous dopamine in the limbic system would be less likely to out-compete the antipsychotic drug. The overall outcome of this scenario is maintenance of antipsychotic efficacy with a reduced risk of EPS [36,66,69]. This hypothesis may explain the low propensity of clozapine and quetiapine to induce EPS [22,38]. However, whether this theory is applicable to other atypical antipsychotics remains to be determined: atypical antipsychotics such as ziprasidone, risperidone and olanzapine have slower dissociation

rates yet are also associated with low EPS induction [51]. Furthermore, since antipsychotics with low binding affinity and high dissociation rates are more sensitive to dopamine secretion, it is plausible that dissociation rates that are too high or affinity for the D2-receptor that is too low, might affect antipsychotic activity and the ability to prevent relapse. Other pharmacological properties may account for the low propensity of atypical antipsychotics to induce EPS. Dissociation from the D2-receptor may also be affected by antipsychotic binding to other receptors, such as 5-HT2A, and it has been proposed that this accounts for the lower levels of EPS observed with atypical antipsychotics compared with conventional antipsychotics [8]. Serotonin is thought to have an important influence on dopamine in that it modulates dopamine release from axon terminals in varying degrees from one pathway to another. Blocking 5-HT2A receptors in the mesocortical, mesolimbic, nigrostriatal and tuberoinfundibular pathways could increase the release of dopamine to such an extent that some of the D2-receptor blockade of an antipsychotic could be reversed. The net effect of this would be the reduction of side effects associated with high D2-receptor occupancy, such as EPS, without attenuating the beneficial effects of antipsychotics in controlling psychotic symptoms [8]. It is, therefore, possible that antagonism of non-D2-receptors such as 5-HT2A might have indirect effects on the dopaminergic system that could affect the ‘hit and run’ D2-receptor antagonism mediated by some atypical antipsychotics. Another theory suggests that blockade of 5-HT2A receptors in the mesocortical and mesolimbic pathways achieves antipsychotic efficacy that supplements the D2-receptor antagonism. These effects would allow for lower atypical antipsychotic doses, which would block less than 80% of the nigrostriatal D2-receptors and would, therefore, reduce the likelihood of EPS [8]. However, a number of factors dispute this theory, including the fact that even at subtherapeutic doses, atypical antipsychotics occupy almost all central 5-HT2A receptors [39,62]. In addition, the likelihood of EPS does not mirror the order of the 5-HT2A/D2 binding affinity ratios for the atypical antipsychotics risperidone, olanzapine and quetiapine [60]. Finally, it should be noted that the potent anticholinergic action of olanzapine and clozapine may provide an additional

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mechanism for reducing the likelihood of EPS [62]. Indeed, it is remarkable that clozapine is able to reverse haloperidol-induced catalepsy in laboratory animals [79], therefore indicating that, in addition to the pronounced sensitivity to dopamine outflow, this atypical antipsychotic also has the ability to counteract EPS induced by the D2-receptor blockade [76,79]. 2.3. Availability of antipsychotic drug to the D2-receptor Studies investigating the D2-receptor occupancy levels and binding properties have highlighted interesting relationships which further our understanding of the mechanism of action of antipsychotic drugs. However, an accurate evaluation of the mechanisms involved in antipsychotic drug therapy should also take into account the fact that D2-receptor occupancy is influenced by the availability of the atypical antipsychotic to the receptor [30]. Antipsychotic plasma level and D2-receptor affinity affect the time-course of dopamine D2-receptor occupancy of an antipsychotic [70]. Oral immediate-release formulations are associated with rapid increases in plasma levels followed by decreases (‘peaks and troughs’). Drug plasma fluctuations may be further augmented in patients who demonstrate low or partial pharmacotherapy-compliance: D2-receptor occupancy fluctuation in relation to drug plasma levels has been demonstrated extensively. Antipsychotics that bind only transiently and relatively loosely to the D2-receptor are associated with a rapid decline in D2-receptor occupancy during the day or following drug withdrawal, while slow dissociating antipsychotics generally maintain sustained levels of D2-receptor occupancy even if plasma drug-concentrations fall [70,72]. Originating from the ‘D2-receptor occupancy threshold’ concept, it might be hypothesized that sustained and long-lasting D2-receptor occupancy above the therapeutic threshold may confer improved therapeutic efficacy. Oral extendedrelease and long-acting injectable formulations offer sustained antipsychotic plasma levels with lower fluctuations between peak and trough plasma levels [19,20], and thus provide useful information in the evaluation of the clinical benefits which arise from stable drug plasma levels. Depot conventional antipsychotics, such as haloperidol decanoate, have shown comparable efficacy in the short term while demonstrating greater advantages versus oral agents in the long term, such as reductions in relapse rates and episodes of hospitalisation [32]. The overall severity of side effects induced by conventional depot agents does not appear to differ from that induced by the corresponding oral formulations which are associated with a major risk of EPS [2]. The recent development of long-acting injectable risperidone microspheres permits the evaluation of the effect of atypical antipsychotics with slow and steady release profiles [17]. The long-acting formulation of risperidone has been shown to achieve lower steady state active drug plasma concentrations over 2 weeks and reduced fluctuations compared with oral risperidone by around 30e40% [17]. Clinical studies have also demonstrated the benefits of long-acting risperidone in terms of prevention of relapse while maintaining the therapeutic

profile associated with atypical antipsychotics, such as low risk of EPS, control of negative symptoms and improved quality of life [25,27,42,43,52]. Although questions remain as to the cost-effectiveness of long-acting risperidone compared with conventional depot antipsychotics [80], two cost-effectiveness models have indicated that long-acting risperidone is cost-effective when compared with either oral agents or the haloperidol depot [16,44]. Data from clinical trials have indicated that treatment with long-acting risperidone is associated with improvements in psychotic symptoms and severity of illness compared with placebo [35] over 12-week and 1-year treatment periods [23,52]. During the 1-year study, the incidence and severity of EPS were low at baseline and decreased during the study period [23]. Moreover, a blind clinical study with optimal controlling of drug compliance among hospitalized patients, showed that long-acting risperidone exhibits similar efficacy compared with oral risperidone, but with improved side-effect profiles, social life ratings and reduced prolactin levels [3]. A PET study using [11C]-raclopride in nine patients with schizophrenia has demonstrated that long-acting risperidone (25 mg and 50 mg) achieves D2-receptor occupancy of above 65% but below 80% at peak plasma levels. Although the D2-receptor occupancy may fall below 65% during ‘trough’ plasma levels (towards the end of the 2-week dosing interval) the risk of relapse does not appear to be increased [57]. Similarly, a small study (n ¼ 8) of patients receiving low-dose depot haloperidol decanoate showed that sufficient relapse prevention was maintained even if D2-receptor occupancy declined to 52% after Week 4 (prior to the next dose) [55]. This evidence does not refute the concept that long-lasting D2receptor occupancy may confer improved therapeutic efficacy; however, it does indicate that larger studies are needed to evaluate whether sustained D2-receptor occupancy above the therapeutic threshold is needed using depot or long-acting formulations. Moreover, further studies are required to clarify whether these observations could be applied to the general schizophrenic patient population, since similar therapeutic plasma levels and D2-receptor occupancy have been also reported for both oral and depot formulations [26]. It could be argued that the improved therapeutic efficacy of depot and long-acting formulations might be related, in part, to their ability to overcome low or partial compliance, since this therapeutic strategy assures prolonged pharmacological coverage and also provides information pertaining to patients’ compliance. From this point of view, it should be noted that the development of new daily-administered formulations that provide low drug plasma fluctuation also appears to support the hypothesis that stable D2-receptor occupancy might provide favourable clinical outcomes. Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic formulated using the osmotic-controlled release oral delivery system (OROSÒ) extended-release technology. The pharmacokinetic profile of paliperidone ER achieves and sustains D2receptor occupancy levels sufficient for antipsychotic efficacy over a 24-h period [40]. Additionally, OROS technology

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delivers a relatively smooth diurnal plasma drug concentrations [10] providing delivery of paliperidone without the rapid rise and fall in concentration characteristic of immediaterelease formulations [40]. In a study of four healthy subjects, a single 6 mg dose of paliperidone ER achieved median D2-receptor occupancy of 64% and 53% at 22 and 46 h after administration, respectively [40]. The D2-receptor occupancy of paliperidone ER at steady state is predicted to show sixfold less fluctuation compared with an immediate-release formulation [40]. These reductions in fluctuations of plasma concentrations might be expected to result in more stable D2-receptor occupancy [40], and may be associated with the demonstrated efficacy and favourable tolerability in patients with acute schizophrenia [13,33,47]. In addition, as with long-acting antipsychotic agents [18], paliperidone ER has the potential to achieve lower antipsychotic plasma levels associated with the desired clinical effects. However, further studies are needed to properly evaluate the clinical benefits of compounds, such as paliperidone ER, that combine stable D2-receptor occupancy with relatively short-term activity. To date, only antipsychotic drugs with high (haloperidol) or relatively moderate (risperidone and paliperidone) D2-receptor affinity are available in slow release formulations. As previously mentioned, the ‘D2-receptor occupancy window’ hypothesis addresses the pharmacological effects mediated by these drugs, while its applicability to fast dissociating antipsychotics continues to be debated. Long-lasting D2-receptor occupation may not be necessary in allowing quetiapine and clozapine to exert their therapeutic effects since these antipsychotics are able to induce clinical alleviation even if only transient D2-receptor occupancy is achieved [21,38]. Alternatively, antipsychotics that bind only transiently and relatively loosely to the D2-receptor are associated with a rapid decline in D2-receptor occupancy following drug withdrawal. In vitro studies have shown that clozapine and quetiapine are displaced from D2-receptors by a physiological concentration of dopamine (100 nM) around 100 times more quickly than olanzapine, haloperidol and other antipsychotics [66]. This has been proposed as a mechanism for the relatively rapid relapse that occurs after discontinuation of antipsychotics such as clozapine (days) [50] and quetiapine [66] compared with the slower relapse (weeks or months) after withdrawal of conventional antipsychotics that bind more tightly, as any sudden surge of impulse-triggered endogenous dopamine will quickly displace any residual clozapine [50,66]. Prolonged blockade of postsynaptic D2-receptors by conventional antipsychotics leading to receptor hypersensitivity has been proposed as one of the mechanisms contributing to the development of tardive dyskinesia [8]. A small PET study has shown that chronic exposure to antipsychotics leads to significant upregulation of D2-receptors in the striatum and, therefore, an increase in antipsychotic binding potential. Those patients with the highest degree of D2-receptor upregulation had associated severe and persistent tardive dyskinesia [67]. Recent studies have argued against this hypothesis, suggesting that other factors related to drug pharmacological

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properties (i.e. impairment of mitochrondia electron transport chain and monoamine oxidase [MAO]-B inhibition) might be involved in the development of tardive dyskinesia [4]. Consistently, long-acting risperidone, devoid of striatal mitochondrial or MAO-B activity, was associated with a low rate of emergent persistent tardive dyskinesia over 1 year of treatment (0.94% at baseline to 1.19% after 1 year) [27]. 3. Conclusions It is generally accepted that atypical antipsychotics are associated with a lower risk of side effects, such as EPS and prolactin elevation, than the older conventional antipsychotics. The ‘D2-receptor occupancy window’ hypothesis or the relatively lower D2-receptor binding within the striatum and the antagonistic activity at 5-HT2A receptors have all been proposed as pharmacological mechanisms by which the antipsychotic activity might combine with a low incidence of side effects. However, each antipsychotic possesses unique pharmacodynamic and pharmacokinetic properties and these differences are reflected in publications that appear to refute these hypotheses starting from the analyses of the receptorbinding profiles. It may also be suggested that stable D2-receptor occupancy is required for consistent and continued antipsychotic efficacy balanced with good safety and tolerability. Although the optimal duration of D2-receptor blockade is still to be determined, evidence from novel formulations of atypical antipsychotics (such as long-acting and extended-release formulations) that deliver consistent and smooth plasma levels over an extended period suggests that this is associated with favourable efficacy and tolerability profiles. However, it has yet to be demonstrated whether stable drug-availability to the D2-receptor might also improve the therapeutic properties of fast dissociating antipsychotics. Additional research, perhaps in preclinical models, is needed to establish the optimal duration of D2receptor occupancy that will lead to improved outcomes for patients with schizophrenia. Acknowledgments The authors would like to thank Samantha Kew, PhD, Medicus International, for her editorial assistance. Editorial assistance was funded by Johnson & Johnson Pharmaceutical Research and Development. In addition, the authors would like to thank ‘‘Regione Automoma della Sardegna’’ for providing financial support (grant project RAS: Anti. Psyc 2005/2006). References [1] ADA. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry 2004;65(2):267e72. [2] Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179:290e9. [3] Bai YM, Chen TT, Wu B, Hung CH, Lin WK, Hu TM, et al. A comparative efficacy and safety study of long-acting risperidone injection and

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