Striatal dopaminergic D2 receptor occupancy and clinical efficacy in psychosis exacerbation: a 123I-IBZM study with ziprasidone and haloperidol

Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 91 – 96 www.elsevier.com/locate/pnpbp

Striatal dopaminergic D2 receptor occupancy and clinical efficacy in psychosis exacerbation: a 123I-IBZM study with ziprasidone and haloperidol Iluminada Corripioa,*, Ana M. Catafaub,1, Vı´ctor Pereza, Dolors Puigdemonta, Esther Menab, ´ lvareza Yolanda Aguilarb,2, Ignasi Carrio´b, Enric A a

Department of Psychiatry, Hospital de la Sta. Creu i St. Pau C/ Sant Antoni Maria Claret 16708025 Barcelona, Spain b Department of Nuclear Medicine, Hospital de la Sta. Creu i St. Pau Barcelona, Spain Accepted 15 October 2004 Available online 23 November 2004

Abstract Objective: The aim of this study was to compare striatal dopaminergic D2 receptor occupancy (D2 RO) induced by ziprasidone and haloperidol and its relationship with clinical response and extrapyramidal side effects (EPS) in patients with acute psychosis exacerbation. Method: Twenty patients hospitalized with an acute psychosis exacerbation were randomised in a single-blind study to receive either ziprasidone (80–120 mg/day) or haloperidol (5–20 mg/day) for more than 2 weeks. When stable doses were achieved, data on 123I-IBZM single-photon emission computed tomography (SPECT), as well as data on clinical efficacy (positive and negative symptoms scale [PANSS]) and EPS (Simpson Angus scale [SAS]), were compared between the two groups of patients. Clinical response was defined as a percentage of change of N30% in PANSS. Striatal D2 RO and clinical data were also compared between responders and nonresponders on each treatment group. Results: All patients on haloperidol and four patients on ziprasidone showed EPS. Mean D2 RO was significantly higher in the haloperidol (74.7F3.5) than in the ziprasidone (60.2F14.4) group (Mann Whitney U-test [M-W U-test] 8.50; p=0.002). Five patients were responders, and five were nonresponders on each group of treatment. Haloperidol responders and nonresponders did not differ in D2 RO, duration of treatment, doses or EPS. Ziprasidone responders were on higher doses than nonresponders and showed higher D2 RO although below 74%. A positive correlation of ziprasidone D2 RO was found with dose (r Spearman 0.87; p=0.001) and with SAS scores (r Spearman 0.88; p=0.001). Conclusions: Ziprasidone induces lower D2 RO and EPS than haloperidol, which is consistent with an atypical antipsychotic profile. A direct relationship of ziprasidone D2 RO with dose, clinical efficacy and EPS has been found in this study. These data suggest that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages. D 2004 Elsevier Inc. All rights reserved. Keywords: Antipsychotics; Dopaminergic receptors; Extrapyramidal side effects; Haloperidol; IBZM SPECT; Schizophrenia; Ziprasidone

Abbreviations: D2R, dopaminergic D2 receptors; D2 RO, D2 receptor occupancy; EPS, extrapyramidal side effects; M–W U-test, Mann Whitney U-test; %RO, percentage of receptor occupancy; PANSS, positive and negative symptoms scale; PET, positron emission tomography; SAS, Simpson Angus scale; SPECT, single-photon emission computed tomography; striatum/occipital cortex uptake (S/O) ratios. * Corresponding author. Tel.: +34 93 2919185; fax: +34 93 2919399. E-mail address: [email protected] (I. Corripio). 1 Current address: Centre for Imaging in Psychiatry Clinical Pharmacology Discovery Medicine Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Barcelona, Spain. 2 Current address: Department of Nuclear Medicine, CRC-Mar, Hospital del Mar, Barcelona, Spain. 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.10.010

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1. Introduction The therapeutic activity of conventional antipsychotics has been largely correlated with the ability of these drugs to antagonize dopaminergic D2 receptors (D2R) in the mesolimbic system measured either by positron emission tomography (PET) or single-photon emission computed tomography (SPECT; Pilowsky et al., 1993; Bigliani et al., 2000). Using these neuroimaging techniques, a therapeutic window of dopaminergic D2 receptor occupancy (D2 RO) between 65% and 70% has been established for most typical antipsychotics, while extrapyramidal side effects (EPS) occur at D2 receptor occupancy above 70% (Farde et al., 1992; Nordstrom et al., 1993; Kapur et al., 2000). This therapeutic window has not been established for atypical antipsychotics, which maintain clinical efficacy even with a low degree of D2 RO and a low incidence of extrapyramidal side effects (EPS; Pilowsky et al., 1992, 1993; Kinon and Lieberman, 1996; Remington and Kapur, 2000). However, differences in the profile of D2 RO between responders to typical and atypical antipsychotics with respect to nonresponders have not been extensively assessed. The present study aims to investigate the striatal D2 RO induced by ziprasidone and haloperidol in patients with acute psychosis exacerbation by means of 123I-IBZM SPECT and to assess its relationship with clinical efficacy and EPS.

own decision, within the 2 weeks prior to hospital admission. None of the patients had received depot neuroleptics during the 6 months prior to inclusion in the study. After written informed consent was obtained, patients were randomised to receive either ziprasidone (n=10) or haloperidol (n=10). Antipsychotic treatment was administered following a two-phase dosage as follows: a first intramuscular administration of up to four injections with a minimum of 2-h interval of ziprasidone (10 mg each) or haloperidol (5 mg each) during the two or three 1st days, followed by a second phase of oral administration of ziprasidone (80–120 mg/day) or haloperidol (5–20 mg/ day), twice daily with meals with a supervised and standardized diet (Stimmel et al., 2002). Doses were flexible and adjusted to each patient’s clinical needs until achievement of stable doses, which were then maintained for at least 15 days before the SPECT scan. Concomitant medication was restricted to benzodiazepines and anticholinergic agents. A single-blind design was followed because of the differences in appearance and volume of ziprasidone and haloperidol intramuscular presentations and difficulties in masking medication. One psychiatrist controlled antipsychotic medication and was blinded to the psychopathologic evaluation, while a second psychiatrist made psychopathological assessments and was blinded to the antipsychotic assigned. Demographic and clinical characteristics of patients for each treatment group are summarized in Table 1.

2. Methods

2.3. Clinical assessment

2.1. Subjects

Clinical status was assessed by means of the positive and negative symptoms scale (PANSS; Kay et al., 1987) at inclusion and on the day of the SPECT performance at stable doses. Clinical response was defined as a percentage of change of N30% in clinical scores (Goff et al., 1998). Presence of EPS was evaluated by means of the Simpson Angus scale (SAS) scores (Simpson and Angus, 1970).

Twenty patients were included in the study (10 males and 10 females, mean age 33.3F7.6 years). Diagnoses according to DSM-IV criteria (American Psychiatric Association Press, 1994) were schizophreniform disorders (n=8) and schizophrenia (n=12). All the patients had been hospitalized within the previous weeks due to an acute exacerbation of their illness. Patients with a history of substance abuse (other than nicotine), past or present neurological disease or any other organic disturbance that might have interfered with the aim of the study were excluded from participation. Pregnancy in female patients was ruled out prior to scanning by negative h-HCG test. Ethical approval was obtained from the local Ethics Committee and Health Authorities, and written informed consent was obtained prior to inclusion in the study. The study was performed in accordance with the Helsinki Declaration of 2000 (World Medical Association, 2000).

2.4. SPECT procedure Brain SPECT was performed 12 h after last antipsychotic dose administration, using 123I-IBZM as ligand for striatal D2R and a double-headed gammacamera (GEMS Helix) equipped with two low-energy and high-resolution collimators. Image acquisition and reconstruction followed the European Association of Nuclear Medicine guidelines for

Table 1 Demographic and clinical characteristics Group

n

Male/female

Diagnosisa

Age meanFS.D. (range)

Haloperidol Ziprasidone

10 10

4/6 6/4

7/3 5/5

36.0F9.0 (26–54) 30.7F5.0 (23–40)

2.2. Treatment All the patients enrolled in the study had discontinued antipsychotic medication during psychosis exacerbation by

a

Diagnosis: schizophrenia/schizophreniform disorder.

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striatal D2R SPECT imaging (Tatsch et al., 2002) and has been described elsewhere (Guardia et al., 2000; Perez et al., 2003). Image acquisition started 90 min after intravenous injection of 5 mCi (185 MBq) of 123-I IBZM (Nycomed– Amersham) flushed with 10 ml of saline. Perchlorate p.o. (8 mg/kg) was administered 20 min prior to the IBZM injection to minimise radiation exposure to the thyroid gland. Thirty-second images were acquired every 68 through a circular orbit of 3608 in a 6464 matrix, with a zoom of 1.5. Following acquisition, images were processed and quantified with an Elscint Xpert computer. For reconstruction, filtered back projection with a Butterworth filter was used, and Chang’s attenuation correction method was applied, with a factor of 0.12. The final pixel size was 4 mm. Two pixel-thick oblique slices in the fronto-occipital direction, as well as coronal and saggital slices, were obtained. For quantification, striatum/occipital cortex uptake (S/O) ratios, which reflect specific/nonspecific binding, were obtained. A standard template of irregular regions of interest (ROIs) for the striatum (mirrored ROIs, one for each hemisphere) and for the occipital cortex (a single ROI including both hemispheres) was used. ROIs were placed on the two consecutive oblique slices that contained the maximum striatal uptake, and averaged mean counts/pixel of the two slices were used for calculations. Percentage of receptor occupancy (%RO) was calculated as a percentage of change of the uptake ratios obtained during antipsychotic treatment related to a mean baseline value, according to the formulae previously reported (Klemm et al., 1996; Tauscher et al., 2002). In this case, the mean S/O ratio obtained in a previous study from nine schizophrenic patients naive of treatment (Perez et al., 2003) was used as mean baseline value for %RO calculation. Psychiatrists were blinded to the SPECT results, and nuclear medicine physicians were blinded to the psychopathological evaluation. 2.5. Statistical analysis SPSS for windows (version 10.0) was used for statistical analysis. Means and standard deviations of S/O ratios were calculated for each group of treatment. The Mann–Whitney U-test (M–W U-test) was used to compare D2 RO between (a) patients on ziprasidone vs. patients on haloperidol and (b) responders vs. nonresponders within each group of treatment. Spearman correlation coefficients were calculated to study the relationship between the degree of striatal D2 RO and doses and between the degree of striatal D2 RO and SAS scores.

3. Results Patients on ziprasidone and on haloperidol were comparable in age and clinical scores at baseline (Table 2). Patients on haloperidol showed higher mean D2 RO (74.7F3.5%)

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Table 2 Comparison of age and clinical scores (meanFS.D.) between haloperidol and ziprasidone groups at baseline and after stable doses (SDS) Group

Age

SAS baseline

SAS SDS

PANSS baseline

PANSS SDS

Haloperidol 36.0F9.0 1.2F1.3 7.8F1.6 79.6F16.5 58.0F6.5 (n=10) Ziprasidone 30.7F5.0 0.8F1.3 3.3F4.3 74.7F9.7 61.1F17.8 (n=10) (M–W (34; 0.25) (42; 0.58) (19.5; 0.02) (46; 0.80) (49; 0.97) U-test; p) M–W U-test—Mann–Whitney U-test; PANSS—positive and negative symptoms scale; SAS—Simpson Angus scale.

than patients on ziprasidone (60.2F14.4%; M–W U-test 8.50; p=0.002; Fig. 1). A positive correlation was found between D2 RO and daily drug doses in the group of patients on ziprasidone (r Spearman 0.87; p=0.001) but not on the haloperidol-treated group (r Spearman 0.25; p=0.49). All patients treated with haloperidol presented EPS, as compared to four out of the 10 patients treated with ziprasidone. SAS scores were significantly higher in the haloperidol than in the ziprasidone group when stable doses were achieved (Table 2). A positive correlation was found between D2 RO and SAS scores in both the haloperidol (r Spearman 0.68; p=0.03) and the ziprasidone group (r Spearman 0.88; p=0.001). Patients on ziprasidone without EPS (n=6) were treated with lower doses and showed lower D2 RO than patients with EPS (Table 3). Five responders and five nonresponders were identified within each treatment group. In the haloperidol-treated group, no significant differences were found between responders and nonresponders in D2 RO, duration of treatment, doses received or EPS. However, responders in the ziprasidone-treated group showed significantly higher D2 RO (69.4F4.5%) than nonresponders (50.4F14.5%), showed more EPS and were receiving higher doses (112F18 vs. 88F18 mg/day) although the difference in doses showed only a trend towards statistical significance with this sample size (Table 4).

4. Discussion 4.1. D2 RO and clinical efficacy This study shows a dose-dependent striatal D2 RO induced by ziprasidone in patients with an acute episode of psychosis and provides evidence that ziprasidone induces lower striatal D2R than haloperidol. All patients on haloperidol showed a high striatal D2R blockade above 68%, being the degree of D2 RO similar between responders and nonresponders. Such high levels of D2 RO have been reported to be reached even with low doses (2–4 mg/day) of haloperidol (Kapur et al., 1996). These results are in agreement with the minimal striatal D2

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I. Corripio et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 91–96 Table 4 D2 RO and clinical data in responders and nonresponders treated with haloperidol and ziprasidone

Fig. 1. Plot of D2 RO vs. treatment. Haloperidol treatment induced significantly higher D2 RO (74.7F3.5%) than ziprasidone (60.2F14.4%; M–W U-test 8.50; p=0.002). Note that the four patients on ziprasidone with EPS showed a D2 ROz70%.

RO threshold reported to be necessary to obtain a clinical response in treatment with classical antipsychotics (Farde et al., 1992). However, in our study, clinical response was not achieved in five patients showing N68% D2 RO. There is evidence that not all patients who achieve this minimal D2 RO degree show a clinical response (Pilowsky et al., 1993), and this could be the case in our patient sample. Other nondopaminergic systems implicated in the pathophysiology of schizophrenia, such as serotoninergic glutamatergic or both, which may interact with dopaminergic circuits (Jentsch and Roth, 1999; Meltzer et al., 2003; Van Der Heijden et al., 2004), as well as D2 RO in extrastriatal sites (Pilowsky et al., 1997; Bigliani et al., 2000; Xiberas et al., 2001), may account for this finding. Extrastriatal D2 RO cannot be appropriately assessed by the ligand used in the present study, 123I-IBZM, because of its relatively low affinity for the striatal D2R (K d=0.43 nM). Due to the low D2 R density in extrastriatal areas, SPECT ligands with high affinity for the D2 R, such as 123I-Epidepride (K i=0.024 nM), are required for the proper assessment of D2 RO in extrastriatal sites.

Table 3 Individual values of D2 RO and doses (mg/day) in patients on ziprasidone with EPS (n=4) and without EPS (n=6) Patients

Presence of EPS

D2 RO

Doses

1 2 3 4 5 6 7 8 9 10

No No No No No No Yes Yes Yes Yes

53.3 66.6 30.6 41.3 60.0 62.3 72.0 70.7 71.0 74.0

80 120 80 80 80 80 120 120 120 120

D2 RO—D2 receptor occupancy; EPS—extrapyramidal side effects.

Treatment

Responders

Nonresponders

Statistical comparison (Mann–Whitney U-test; p)

Haloperidol n D2 RO Duration of treatment Doses SAS

5 75.1F3.0 17.0F3.7 10F6 7.8F1.6

5 74.3F4.2 20.0F6.6 15F5 7.2F1.6

(11.0; 0.8) (10.0; 0.7) (6.0; 0.2) (8.5; 0.4)

Ziprasidone n D2 RO Duration of treatment Doses SAS

5 69.4F4.5 16.0F2.4 112F18 6.6F3.7

5 50.4F14.5 14.7F0.5 88F18 0.0F0.0

(1.0; (7.5; (5.0; (2.5;

0.02) 0.3) 0.07) 0.02)

D2 RO—D2 receptor occupancy; M–W U-test—Mann–Whitney U-test; SAS—Simpson Angus scale.

In the present study, ziprasidone clinical response was related to the degree of D2 RO in agreement with previous studies suggesting that a minimal striatal D2R blockade is necessary to obtain a clinical response in treatment with atypical antipsychotics (Remington and Kapur, 2000). It has been sustained that the alternative bfast-offQ atypical hypothesis (Kapur and Seeman, 2001) applies only to clozapine and quetiapine, being inconsistent with the bslowQ off rate of most atypical antipsychotics, including olanzapine, risperidone and ziprasidone (Meltzer et al., 2003). Therefore, it can be assumed that the D2 RO reported in this study, which was measured 12 h after the last ziprasidone dose administration after at least 2 weeks of treatment, is stable over time. In this study, patients responding to ziprasidone received higher doses and showed higher mean D2 RO than nonresponders. Moreover, a positive correlation of D2 RO and dose was found. A dose-dependent D2 RO by ziprasidone has been previously reported after a single dose escalation study in healthy volunteers (Bench et al., 1993). However, a recent study has failed to replicate this result, although drug ingestion was not supervised, and standardized diet was not proposed to the patients (Mamo et al., 2004). Furthermore, a dose-dependent reduction in psychotic symptoms with ziprasidone has been proposed in acute exacerbation of schizophrenia, particularly at dose range of 120–160 mg/day (Daniel et al., 1999; Keck et al., 1998, 2001). The present study supports these previous data in a population of acutely psychotic patients using 80–120 mg/day doses of ziprasidone. 4.2. D2 RO and EPS In this study, all patients on haloperidol presented EPS. All were treated with high doses, showing a striatal D2R blockade above 68%. This finding is consistent with the

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minimal threshold of 70% D2 RO proposed for appearance of EPS with typical antipsychotics (Farde et al., 1992; Pilowsky et al., 1993). Ziprasidone showed a more favourable profile in EPS than haloperidol. The four ziprasidone-treated patients with EPS showed D2 ROz70% (Fig. 1). Moreover, patients on ziprasidone without EPS (n=6) were treated with lower doses and showed lower mean D2 RO than patients with EPS (n=4). Ziprasidone is a 5-HT1A receptor agonist and a potent 5-HT2/D2 receptor antagonist with an 11:1 binding affinity, the highest ratio among available antipsychotic agents (Arborelius et al., 1993). Experimental and clinical evidence suggests that 5-HT2A antagonism and 5HT1A agonism reduce neuroleptic-induced extrapyramidal effects. Such a mechanism enhances dopamine release in the basal ganglia and have been proposed for in vitro studies as desirable in an antipsychotic agent as it may reduce EPS (Sharma, 1996). Increased striatal dopamine levels may cause reduced 123I-IBZM binding (Laruelle et al., 1999), and this might explain at least in part the lower striatal D2 RO found in the ziprasidone-treated group, which seem to account for the lower incidence of EPS in this group. A positive correlation between %RO and SAS scores was found both in the ziprasidone- and haloperidol-treated groups. In agreement with these results, a direct relationship between D2 RO and EPS has been reported in studies with typical and atypical antipsychotics, such as haloperidol (Pilowsky et al., 1993), risperidone (Knable et al., 1997) and olanzapine (Tauscher et al., 2002). This relationship has not been found with other atypical antipsychotics, such as clozapine or quetiapine (Kufferle et al., 1997; Tauscher et al., 2002). The low propensity to induce EPS by quetiapine and clozapine has been explained by their relatively low striatal D2 RO (Kapur et al., 2000). The serotonin–dopamine modulation has been proposed as a protective mechanism against EPS for risperidone and olanzapine at low levels of D2 RO (Meltzer et al., 2003). However, at high D2 RO, the 5HT2A blockade does not seem protect against EPS, and the threshold of D2 receptor occupancy associated with EPS is similar to that found in typical antipsychotics (Kapur et al., 1995, 1999; Knable et al., 1997). The results in this study suggest that a likely mechanism might apply to ziprasidone.

5. Conclusions Ziprasidone induces lower D2 RO and EPS than haloperidol in patients with acute psychosis exacerbation, which is consistent with an atypical antipsychotic profile. The direct relationship of ziprasidone D2 RO with dose, clinical efficacy and extrapyramidal side effects found in this study suggests that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages.

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Acknowledgements This study was supported by a grant from Pfizer and by Spanish Fondo de Investigaciones Sanitarias FIS 00/0335. The authors thank Carolyn V. Newey for her editing assistance.

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