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Original Paper 169
Striatal D2/D3 Receptor Occupancy, Clinical Response
and Side Effects with Amisulpride:
An Iodine-123-Iodobenzamide SPET Study
Authors
E. M. Meisenzahl1, G. Schmitt1, G. Gründer3, S. Dresel2, T. Frodl1, C. la Fougère2, J. Scheuerecker1,
M. Schwarz1, R. Boerner1, J. Stauss2, K. Hahn2, H.-J. Möller1
Affiliations
1
Department of Psychiatry, LMU University of Munich, Munich, Germany
Department of Nuclear Medicine, LMU University of Munich, Munich, Germany
3
Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany
Abstract
&
Introduction: Amisulpride appears to be an
effective atypical agent for treating schizophrenia in a dose-dependent manner.
Methods: 29 patients suffering from schizophrenia or schizoaffective disorder were treated
with a broad dose range of amisulpride (50–
1 200 mg/day, mean: 455.2 ± 278.8 mg/day). After
2 weeks, brain single photon emission tomography (SPET) scans were performed two hours after
intravenous injection of 185 MBq [123I]IBZM.
Clinical evaluations and ratings of extrapyramidal symptoms were performed at baseline and
after steady state treatment of two weeks with
amisulpride.
Introduction
&
received
revised
accepted
24.10.2007
30.01.2008
12.02.2008
Bibliography
DOI 10.1055/s-2008-1076727
Pharmacopsychiatry 2008;
41: 169–175
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0176-3679
Correspondence
E. M. Meisenzahl, MD
Department of Psychiatry
Ludwig-Maximilians-University
of Munich
Nussbaumstraße 7
80336 Munich
Germany
Tel.: + 49/89/5160 24 23
Fax: + 49/89/5160 45 55
[email protected]
Amisulpride is a substituted benzamide which
has a unique binding and clinical profile, with
high affinity for dopamine D2 and D3 receptors
but none for D1, D4 and D5 receptors or adrenergic, serotonergic or histaminergic receptor systems. This pharmacological profile means that
amisulpride has advantages with regard to side
effects, with a lower incidence of hypotension,
anticholinergic and sedative effects and EPS
[11, 21]. A recent meta-analysis of 18 clinical trials
showed that amisulpride is an effective and welltolerated atypical antipsychotic for the treatment
of both positive and negative symptoms [8].
Up to now, there are different models about the
mechanisms of the atypical action of amisulpride.
It may be related to its preferential autoreceptor
binding, especially at low doses. Alternatively, its
preferential interaction with the limbic dopaminergic system may give it the benefit of atypicality.
Amisulpride seems to have a particular affinity for
limbic D2 dopamine receptors. Studies in rodents
have shown that amisulpride is 2.5-fold more
Results: In patients treated with amisulpride,
specific binding of [123I]IBZM to D2 receptors
was significantly decreased (p < 0.001) compared
to healthy controls. D2 receptor blockade correlated well with administered doses and plasma
concentrations of amisulpride. Extrapyramidal
side effects, which had to be treated with biperiden, were observed in 31 % of the patients. Clinical response was very good, without correlation
between the response and striatal D2 occupancy.
Discussion: Within the first two weeks of treatment with the atypical antipsychotic amisulpride
a significant occupancy of striatal postsynaptic
dopamine D2 receptors was achieved. At the
same time amisulpride shows an excellent tolerability with good efficacy.
potent at inhibiting the binding of 3H-raclopride
in the limbic system than in the striatum [17].
Finally, as amisulpride rapidly dissociates from
the dopamine D2 receptor, its atypicality may be
explained by the fast dissociation hypothesis of
atypicality from Seeman and Kapur [6].
Despite the need to clarify the in vivo mechanism
of action, up to now only a few investigations
have been performed to investigate the striatal
and extrastiatal D2 receptor occupancy during
amisulpride treatment [2, 4, 9, 20, 22].
As previous studies, due to different dosage
regimes and small sample sizes, obtained different
results concerning the D2 binding of amisulpride,
our present investigation aimed to evaluate by
means of SPET the striatal D2/D3 receptor occupancy of a broad range of dosages of amisulpride,
between 50 mg and 1 200 mg daily, in a large sample of patients [4]. Beside the obtained D2/D3
bindings [4], another highly relevant objective was
to evaluate the clinical response to and possible
side effects of amisulpride. An exploratory analysis
of the relationship between clinical response and
striatal D2/D3 occupancy was performed.
Meisenzahl EM et al. Striatal D2/D3 Occupancy, Clinical Response … Pharmacopsychiatry 2008; 41: 169–175
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2
170 Original Paper
The study included consecutively admitted inpatients LMU (19
males, 10 females) from the Department of Psychiatry at the
University of Munich, who were suffering from schizophrenia
(N = 26) or schizoaffective disorder (N = 3) (DSM IV). Their mean
age was 31.7 years (31.7 ± 12.2 years, range: 19–68 years). All
patients received continuous monotherapy with amisulpride in
a prospective, open study design. Medication was given according the clinical needs and was chosen by the respective attending clinician. Medication remained stable over 14 days. None of
the patients was receiving any other concomitant antipsychotic
substance, and no depot formulation had been used previously.
Permissible concomitant medication was restricted to biperiden, zopiclon and lorazepam.
Before the SPET investigation, all patients had been treated
with amisulpride in a daily dose between 50 and 1 200 mg/day,
with a mean dose of 455.1 ± 278.8 mg/day (6.07 ± 3.94 mg/kg
body weight). The last medication was given 12–14 hours before
the SPET. Patients pretreated with other antipsychotics underwent a wash-out period from prior treatment of 3 days duration
before starting the monotherapy with amisulpride. Eleven of the
29 patients were pretreated with psychotropic medication
before the wash-out period (four patients with olanzapine, two
with clozapine, two with risperidone, one with perazine, one
with paroxetine and one with lorazepam). All others had had no
intake of medication for at least 3 months.
In 28 of the 29 patients, plasma levels of amisulpride were
assessed just before the SPET investigation was performed.
The mean plasma concentration was 200 ± 182 ng/mL (range:
26.5–910 ng/mL).
According to the diagnostic criteria (DSM IV), 26 patients were
diagnosed as suffering from schizophrenia, and 3 from schizoaffective disorder. None of the patients had a second psychiatric
disease or any dependency on drugs and alcohol. The assessment of psychopathology was performed at baseline and after
14 days of steady-state treatment using CGI, BPRS, PANSS and
SANS scales. The Extrapyramidal Symptom Rating Scale (ESRS)
and the Barnes Akathisia Scale (BAS) were used to assess
extrapyramidal symptoms after 14 days of steady-state treatment with amisulpride. The response criterion was a reduction
of 30 % of the baseline scores of PANSS and SANS.
Ethical approval for the SPET investigation was provided by the
local ethics committee, all patients had given informed written
consent prior to the study.
SPET investigation
Each subject was injected with 185 MBq [123I]IBZM intravenously 12–14 hours after the last amisulpride intake. Two hours
after radiotracer administration, SPET acquisitions were performed over a period of 50 minutes. A Prism 3000 XP triple
headed gamma camera (Picker, Cleveland, Ohio) equipped with
high resolution fan beam collimators was used for SPET image
acquisition.
The acquisition parameters included a 20 % energy window centered on 159 keV, a rotational radius of 13 cm or less, 120 projection angles over 360 degrees, and a 128 × 128 matrix with a pixel
width of 2.11 mm in the projection domain. The projection
images were reconstructed by filtered back projection and filtered by a low pass filter, Chang’s first order method was
used for uniform attenuation correction. Images were uniformly
re-sliced by drawing a line connecting the anterior-most aspect
of the frontal pole to the posterior-most aspect of the occipital
pole, which approximates the line connecting the anterior and
posterior commissures (AC-PC line). The control group utilized
for this study consisted of ten healthy age- and sex-matched
subjects (six males, four females, age 32.4 years, range: 22–58
years).
In order to assess specific tracer uptake in the striatum, we used
the region of interest (ROI) technique. For each patient, data
were evaluated in the 2 consecutive transverse slices showing
the highest tracer accumulation in the basal ganglia, and then
the arithmetic mean of these 2 slices was calculated. Mean specific binding (SB) in the basal ganglia regions was calculated
according the following equation:
SB = (STR − BKG)/BKG
where STR and BKG are the mean counts per pixel in the striatum and frontal cortex as background, respectively. Templates
were used to define the striatal ROIs. The size and shape of the
templates was established and optimized using the control data.
The non-specific background activity was estimated by drawing
an ROI around the frontal cortex. Mean specific binding values of
a normal control group were used to calculate the striatal
dopamine D2 receptor occupancy:
D2 occupancy = [(SBcontrol − SBpatient )/SBcontrol ] ×100%
Measurement of amisulpride plasma concentrations
The detection of amisulpride was performed via an isocratic
reversed-phase high-performance liquid chromatography (HPLC)
separation and ultraviolet (UV) detection at 280 nm and 195 nm.
The HPLC system consisted of a Waters 515 pump, a Waters 717
auto sampler and a Waters 2487 dual wavelength UV detector
(Waters, Milford, MA). The chromatographic separation was
achieved by using an end-capped C8 reversed-phase HPLC column (Merck, Darmstadt, Germany) connected with a guard column (Merck, Darmstadt, Germany). Benperidole, kindly provided
by Bayer Healthcare (Leverkusen, Germany), was used as the
internal standard. Amisulpride was kindly provided by SanofiSynthelabo GmbH (Berlin, Germany). A stock solution of the
analyte (1 mg/mL) was prepared in methanol and added to
human drug-free serum obtained from healthy donors to establish five different calibration concentrations, ranging from 50 to
1000 ng/mL, and three different control sample concentrations
(50, 400, 800 ng/mL). The five-point calibration curves were
plotted by the peak-high ratios of the analyte/internal standard
versus concentrations of the analyte in serum. Regular participation in an external quality control scheme (Health control,
Cardiff, UK) guaranteed the specificity of the analysis.
Statistical analysis
Statistical analyses of SPET measurements and the clinical outcome data of amisulpride-treated patients and controls were
performed using one-way analysis of variance (ANOVA). Posthoc tests (Scheffe) were used to test significance of differences.
Student’s t-test was performed to compare two independent
groups. Equality of variances was tested using Levene’s test of
equality of variances. Continuous values were correlated using
Pearson correlation coefficients, and discrete values using the
Spearmens’s Rho coefficients.
Plasma concentrations at time of injection and D2/D3 receptor
occupancy values were fit to a one site ligand binding model by
Meisenzahl EM et al. Striatal D2/D3 Occupancy, Clinical Response … Pharmacopsychiatry 2008; 41: 169–175
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Patients and Methods
&
Subjects
Original Paper 171
14 days
significance
steady state
age
gender
dose amisulpride
plasma levels
weight
CGI (0–7)
BPRS (0–126)
PANSS (0–210)
SANS (0–120)
EPS
parkinsonism
dyskinesia
dystonia
(STR-BKG/BKG)
D2 occupancy rate
31.7 ± 12.2 y
19 m/10 f
50–1200 mg
200.3 ± 181.5 ng/mL
73.9 ± 13.5
5.8 ± 0.64
64.4 ± 10.0
105.6 ± 18.2
58.2 ± 16.8
75.3 ± 13.6
4.3 ± 1.02
42.8 ± 11.7
73.9 ± 20.9
48.0 ± 18.2
0.0001
0.0001
0.0001
0.0001
0.03
80
60
40
20
0
0
1.6 ± 3.9
4.7 ± 7.8
0.12 ± 0.5
0.43 ± 0.32
73.3 % ± 13.7
non-linear regression analysis using Sigma Plot, Version 9.0, to
the following equation:
Occupancy [%] = (Emax ×[C Ami ])/(EC50 +[C Ami ])
where Emax is the maximum attainable receptor occupancy, EC50
is the plasma concentration predicted to provide 50 % of the
maximum attainable receptor occupancy and CAmi is the plasma
concentration of amisulpride.
Data were considered to be significant when p < 0.05.
Results
&
D2/3 receptor binding and amisulpride plasma levels
All patients treated with the novel antipsychotic amisulpride
showed a reduced striatal IBZM D2 binding in comparison to
untreated healthy controls (t = 14. 9, p < 0.0001) (䊉䉴 Table 1).
The mean dosage of amisulpride was 455.1 ± 278.8 mg daily. Striatal IBZM binding of the patient group, expressed as [STR–BKG]/
BKG, ranged from 0.0–1.12 (mean 0.43 ± 0.32) versus a mean
striatal IBZM binding of 0.95 ± 0.10 (range: 0.78–1.12) for the
healthy control group. No differences were found between the
treatment group and the comparison group in terms of age
(p = 0.62) or gender (p = 0.88). Additionally, no statistical differences emerged between the pretreated patient group (N = 11)
and the non-pretreated patient (N = 18) group for any sociodemographic item (age: p = 0.33, weight: p = 0.65) or psychopathological rating at baseline (PANSS: p = 0.84, SANS: p = 0.30,
ESRS Parkinsonism: p = 0.17, ESRS dystonia p = 0.20, ESRS dyskinesia: p = 0.98) or striatal D2 receptor occupancy after 14 days of
steady state treatment (p = 0.21).
In the patient group, individual striatal D2 receptor occupancy
ranged from 42 to 100 % with a mean value of 73 ± 14 %. The average occupancy was 42 % for 50 mg (N = 1), 55 % for 100 mg (N = 2),
58 % for 150 mg (N = 1), 71 % for 200 mg (N = 2), 73 % for 300 mg
(N = 8), 70 % for 400 mg (N = 3), 81 % for 500 mg (N = 2), 79 % for
600 mg (N = 3), 81 % for 800 mg (N = 6) and 93 % for 1 200 mg
(N = 1). When dopamine D2/D3 receptor occupancy and amisulpride daily dose were related to each other according to the law
of mass action, the two parameters were highly significantly
200
400
600
800
1000 1200 1400
Amisulpride Daily Dose [mg]
Fig. 1 Dopamine D2/D3 receptor occupancy highly significantly
correlated with amisulpride plasma concentration at the time of the SPET
scan.
100
80
60
40
20
0
0
200
400
600
800
1000
Amisulpride Plasma Level [ng/ml]
Emax = 90%
EC50 = 30 ng/ml
Fig. 2 Dopamine D2/D3 receptor occupancy highly significantly
correlated with amisulpride daily dosage at the time of the SPET scan.
correlated (R = 0.70; 䊉䉴 Fig. 1), with an Emax value of 87 %
(p < 0.0001) and an ED50 of 60 mg (p = 0.0028).
The amisulpride plasma concentration was measured in 28 of
the 29 patients and showed a mean of 200 ng/mL ± 182 (range:
27–910 ng/mL). There was a significant positive correlation
between the amisulpride dose at steady state and amisulpride
plasma levels (r = 0.54, p = 0.003). Dopamine D2/D3 receptor
occupancy highly significantly correlated with amisulpride
plasma concentration at the time of the SPET scan (R = 0.63,
䉴 Fig. 2), with an E
䊉
max value of 90 % (p < 0.0001) and an ED50
value of 30 ng/mL (p = 0.0047) (䊉䉴 Fig. 2).
The D2/D3 measurements were checked for possible confounding factors of comedication: the effect of biperiden on D2/D3
binding (p = 0.26) and the effect of the benzodiazepines on
D2/D3 binding was not significant (p = 0.19).
Side effects: EPS
Of the 29 patients, 16 (55.1 %). developed mild extrapyramidal
symptoms (EPS). After the treatment with amisulpride, the
scores on the ESRS for symptoms of Parkinsonism (scores 0–48)
Meisenzahl EM et al. Striatal D2/D3 Occupancy, Clinical Response … Pharmacopsychiatry 2008; 41: 169–175
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Baseline
D2/D3 Receptor Occupancy [%]
Patients
100
D2/D3 Receptor Occupancy [%]
Table 1 Demographic and psychopathological variables of patients at baseline and after 14 days of steady state treatment with amisulpride
(mean: 1.6 ± 3.9), dyskinesia (scores: 0–42) (4.7 ± 7.8), dystonia
(scores 0–96) (mean: 0.12 ± 0.55) and BAS (scores: 0–14) (mean:
0.86 ± 1.86) appeared quite low. Antiparkinsonian medication
(biperiden) was necessary in 9 of the 29 patients (31.0 %). The
treatment with biperiden had no influence on the EPS scores
after 14 days (ESRS Parkinsonism p = 0.64, ESRS dykinesia p = 0.13,
ESRS dystonia p = 0.07). Additionally, 10 patients were treated
temporarily with lorazepam.
EPS, D2 receptor occupancy and dosage
Within the group of patients with EPS, the D2/D3 receptor binding was 77 ± 13 % (range: 51–100 % D2 blockade), which was
higher than in those without EPMS, who showed a D2 blockade
of 69 ± 13 % (range: 42–86 %). This difference did not reach statistical significance (p = 0.12). There was a significant difference in
the daily dosage of amisulpride between the subgroups of
patients with (mean dosage 591 mg ± 272) and those without
EPS (mean dosage 288 ± 185) (p = 0.002).
There was no correlation between the EPS subscales and D2
receptor occupancy (ESRS Parkinson r = 0.003, p = 0.98; ESRS
dyskinesia r = − 0.21, p = 0.28; ESRS dystonia r = 0.20, p = 0.29).
Clinical efficacy
The psychopathology of the patients at baseline was assessed
with BPRS (64.4 ± 10. 04), PANSS (105.6 ± 18.2), SANS (58.2 ± 16.8)
and CGI (5.8 ± 0.64). After 14 days of steady state treatment, in all
three scales there was a significant improvement (PANSS
p < 0.0001, PANSS Positive subscale p < 0.0001 and SANS p < 0.001)
of psychopathology (䊉䉴 Table 1).
Regarding psychopathology, in the comparison between the subgroups of patients treated with lower dosage (LD) of amisulpride
(50–300 mg amisulpride/daily) in comparison to the patients
treated with higher dosages (HD) (400–1 200 mg amisulpride/
daily), the ratings show that the patients treated with higher dosages had higher scores at the beginning of the study, in all
psychopathological items including the productive and the negative symptoms dimensions (CGI HD 6.1 ± 0.7, LD 5.6 ± 0.4; BPRS HD
67.2 ± 8.7; LD 61.5 ± 10.7; PANSS 110.4 ± 15.7, LD 100.5 ± 19.9; SANS
HD 63.4 ± 15.0, LD 52.6 ± 17.3) reaching marginal significance for the
CGI (p = 0.057). After two weeks of steady state treatment, the distribution of the responders was as follows: PANSS: 14 responders/15
non-responders (response rate 48.3 %), PANSS Positive subscale: 18
responders/11 non-responders (response rate 62.1 %) SANS: 9
responders/20 non-responders (response rate 31 %). No differences
regarding clinical improvements between the groups treated with
high and low dosages of amisulpride emerged for the PANSS scale
(p = 0.60) and the BPRS (p = 0.55) and the SANS (p = 0.07).
Response was not influenced by pretreatment with psychotropic
medication (PANSS: p = 0.81, PANSS Positive Subscale: p = 0.89,
SANS: p = 0.62) or by additional comedication with benzodiazepines (PANSS: p = 0.12, PANSS Positive Subscale: p = 0.11,
SANS: p = 0.66) or antiparkinsonian medication (PANSS p = 0.06,
PANSS Positive Subscale p = 0.64, SANS p = 0.50).
Clinical response and D2 receptor occupancy
No differences emerged between the responder and nonresponder (NR) groups on the PANSS scale, with respect to the
D2 receptor occupancy (responder group: 73.6 % ± 13. 9 vs. nonresponder 72.9 % ± 14.0, p = 0.89), plasma level of amisulpride
(responder group 172.1 ± 95.8 vs. NR 224.7 ± 233.7, p = 0.45) or
intake dose per mg daily (responder 410.7 mg/d ± 223.0 vs. NR
496.6 mg/d ± 324.2 , p = 0.41).
The same was true for the PANSS Positive Subscale and the D2
receptor occupancy (responder group: 73.7 % ± 14.2 vs. nonresponder 72.4 % ± 13.4, p = 0.80), plasma level of amisulpride
(responder group 197.7 ± 120.3 vs. NR 204.4 ± 256.5, p = 0.92),
intake dose per mg daily (responder 486.1 mg/d ± 247.2 vs. NR
404.5 mg/d, p = 0.45), and the SANS scale and D2 receptor
occupancy (responder group: 68.4 % ± 18.3 vs. non-responder
75.4 % ± 10.9, p = 0.20), plasma level of amisulpride (responder
group 173.3 ± 164.4 vs. NR 211.1 ± 190.9, p = 0.62) and intake
dose per mg daily (responder 338.8 mg/d ± 236.8 vs. NR
507.5 mg/d ± 285.7 , p = 0.13).
In an exploratory analysis, the clinical response after 14 days
of steady state treatment and the D2 receptor occupancy of
amisulpride was correlated. The clinical improvement was
calculated by the following procedure: [PANSSBaseline score–
PANSSFollow-up score 14 days].
The value achieved was correlated with the D2/D3 receptor
binding and showed no significant correlation with the Spearman’s rho (r = 0.07; p = 0.70).
Discussion
&
We investigated the striatal D2/D3 receptor occupancy of a
broad range of dosages of amisulpride between 50 mg and
1 200 mg daily in a large sample of patients with schizophrenia
after steady state treatment of 2 weeks. The mean dosage of
455 mg daily of amisulpride achieved a relatively high mean
D2/3 receptor binding of 73 % in the striatum. We determined an
EC50 value of 30 ng/mL with regard to amisulpride plasma concentration and an EC50 of 60 mg with regard to amisulpride daily
dose.
D2/D3 binding of amisulpride
Amisulpride is an atypical antipsychotic drug with selective
affinity for D2/D3 dopamine receptors and thus provides an
excellent pharmacological model for testing the hypothesis of
atypical action in the CNS. The valid evaluation of in vivo striatal
D2/D3 binding is an important piece of the puzzle towards a better understanding of antipsychotic drug action [24]. Our study
aimed to contribute to the question of the extent of striatal
D2/D3 receptor binding of amisulpride.
When comparing the striatal D2/D3 occupancy rates of all studies available [2, 9, 19, 20, 22] including our own results [4], there
are marked differences regarding the D2 binding of the drug.
A variety of methodological and clinical aspects has to be taken
into account when comparing striatal D2 occupancy results of
studies. First of all, the usage of different methods such as SPET
and PET makes comparison difficult. Additionally, the application
of differently affine ligands and the specific modeling applied to
the acquired data have to be borne in mind. The time point of data
acquisition after the last ingestion of medication is critical, if
plasma concentrations of the investigational drug are not available. From a clinical viewpoint, a variety of clinical variables have a
notable influence on results, such as the selection of the control
group, the drug dosage investigated, the group size and their clinical characteristics with medical pretreatment, age and sex. The
duration of drug treatment is probably also a relevant factor.
The earliest PET study on the D2 binding of amisulpride was
performed with a relatively low mean dose of 205 mg (range:
50–800 mg). The mean striatal D2 binding achieved by use of
the ligand [76Br]bromolisuride was 30 % with a range between
Meisenzahl EM et al. Striatal D2/D3 Occupancy, Clinical Response … Pharmacopsychiatry 2008; 41: 169–175
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172 Original Paper
4 and 76 % [9]. The same research group applied the highly affine ligand [76Br]FLB 457 with an only slightly higher mean dosage of 278 mg daily (range: 25–1 200 mg) of amisulpride. In
this second investigation, an even lower mean D2 binding of
25 % and a range of 0 to 62 % was detected [22, 23]. In contrast,
Vernaleken et al. [20] using PET with [18F]desmethoxyfallypride demonstrated a significantly higher striatal D2/D3 occupancy, with a mean value of 67 % (43–85 %) in the putamen
and 76 % (67–90 %) in the caudate [19]. Evident discrepancies
between these investigations are the medication ranges administered with the highest doses used in the latter study and the
timing of the PET scan relative to the last drug administration.
In the study by Vernaleken et al. the timing of the PET scan was
close to tmax of amisulpride. However, at comparable amisulpride plasma concentrations, Xiberas et al. [22, 23] report markedly lower striatal D2 receptor occupancies than Vernaleken
et al. [20]. The latter authors attribute the overt discrepancy to
an underestimation of striatal D2 occupancy in the study by
Xiberas et al., because these authors most likely measured striatal binding of their tracer not at equilibrium [15].
The only published SPET study on the D2/D3 binding characteristics of amisulpride in eight patients used [123I]epidepride
as the radiotracer [2, 19] [123I]. Epidepride is a high affinity ligand, which allows for the quantification of extrastriatal D2
receptors also. Bressan et al. documented a mean striatal D2
occupancy of 56 % with individual values ranging from 19 to
75 % [2], which seem to be somewhat lower than the values
reported here. However, the studies by Bressan et al. [2], Martinot et al. [9], Vernaleken et al. [20], and ours have in common
that they report markedly higher striatal D2/D3 receptor occupancies than the study by Xiberas et al. [22, 23]. These four
studies consistently show that striatal occupancy increases
dose-dependently and that the 80 % EPS threshold is crossed at
high plasma concentrations.
Our data can be reliably compared with those documented by
Bressan et al. [2] and Vernaleken et al. [20], when brain binding
data and plasma concentrations are related to each other
according to the law of mass action [Martinot et al. [9] did not
report plasma concentrations]. The time-course of dopamine
D2 receptor occupancy of an antipsychotic is a function of its
plasma pharmacokinetics and in vivo affinity. Thus, regardless
of the time of the PET scan relative to the last drug administration, the estimated data can be described by a non-linear fit
describing a one site saturation. While all three studies reveal
an Emax close to total saturation of D2/D3 receptors, the reported
EC50 values are somewhat different. Bressan et al. [2] calculated an EC50 of 206 ng/mL for the total striatum from a sample
of only six subjects, while Vernaleken et al. [19] in their sample
of nine patients found an EC50 of 144 ng/mL for the putamen
and 60 ng/mL for the caudate. In our large sample we determined an EC50 of 30 ng/mL. Assuming a “therapeutic window”
for antipsychotic drug action between 60 and 80 % striatal D2/D3
receptor occupancy, it can be calculated from our EC50 value that
60 % of the striatal D2/D3 receptors are occupied at an amisulpride plasma concentration of 60 ng/mL, and that the 80 %
threshold is passed at 240 ng/mL. Müller et al. in a large sample
of 378 patients treated with amisulpride found that the optimal amisulpride plasma concentrations to avoid non-response
and EPS were in the range between 100 and 320 ng/mL [13].
Consequently, while the plasma concentrations, which are predicted by means of [123I]IBZM SPET to have the best efficacy/
safety ratio, are somewhat lower than those found in clinical
practice, the two available PET studies slightly underestimate
the striatal D2/D3 receptor occupancy at the most suitable
clinical doses, with the study by Bressan et al. [2] documenting
the lowest occupancy values. The most likely explanation for
these discrepancies is the different affinity of the used radiotracers, with [123I]epidepride having the highest affinity, making this tracer probably less likely to be sensitive to competition
with other ligands.
It is noteworthy, that discrepant treatment durations might also
influence D2 receptor occupancy as measured with nuclear
imaging technology. While we measured D2 blockade after 14
days steady state treatment, Bressan and colleagues studied
patients who had been treated between 21 and 348 days. While
it is clear that treatment with psychotropic drugs changes receptor availability over time, study of the dynamics of these processes in the human brain has as yet been completely neglected
in nuclear imaging.
The picture is further complicated by the finding of a regionspecific differential binding of amisulpride. The two imaging
studies that evaluated the D2 occupancy of amisulpride in striatal and extrastriatal brain regions showed a significantly higher
occupancy of the agent in extrastriatal than in striatal regions
[2, 22, 23]. However, while the study by Xiberas et al. [22, 23] has
been criticized for its methodological flaws [15, 20], the discrepancy between striatal and extrastriatal binding is much less pronounced in the study by Bressan et al. [2]. Olsson and Farde [15]
extensively discussed factors that influence these findings, such
as ligand affinity and the different time of binding equilibrium
in different brain regions with different D2 receptor density. The
time of the scan relative to the last drug administration is only
relevant when drug plasma concentrations are not available [3].
Clinical side effects
The second aim of the study was to evaluate emerging clinical
side effects during the first 14 days of treatment with a large
dose range up to 1 200 mg daily of amisulpride.
The D2 occupancy rate achieved a mean of 73 % with a maximum D2 occupancy of 100 %. 55 % of the patients experienced
EPS, mostly mild in severity. 9 out of 29 patients (31 %) had to
be treated with the anticholinergic agent biperiden. Therefore,
our data are in accordance with the SPET study by Bressan,
who found a favorable extrapyramidal symptom profile after
treatment with a mean dose of 406 mg amisulpride daily for
190 days.
Based on basic research and in vivo imaging studies, two mechanisms could explain the atypicality of amisulpride; preferential
action on limbic D2/D3 receptors and preferential blockade of
presynaptic D2/D3 autoreceptors [28]. In addition, the fast dissociation hypothesis can contribute to the explanation of the
atypical clinical profile of amisulpride [11, 18].
The patients who experienced extrapyramidal side effects had a
range of D2 occupancy between 51.3 and 100 % D2 blockade and
a mean of 76.8 %. As the mean value in this subgroup exceeded
the threshold for EPS suggested by Farde, whereas the patients
without EPS revealed a mean D2 blockade of 68.9 %, statistically
our data support the concept of Farde of a certain threshold in
D2 occupancy for EPS symptoms.
Finally, the correlation between D2 occupancy and EPS rates was
not confirmed in our data. This was probably due to the very low
rating scores overall with Parkinson symptom scores of 1.6, dyskinesia scores of 4.7 and dystonia scores with 0.12.
Meisenzahl EM et al. Striatal D2/D3 Occupancy, Clinical Response … Pharmacopsychiatry 2008; 41: 169–175
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One clear limitation in any open trial including ours is that the
rater is not blinded for the dosage of the medication. This aspect
has to be taken clearly into account.
The most frequent primary requirement for atypicality is primarily the low risk of extrapyramidal side effects. Observations
from psychopharmacological research define the combined
5HT2/D2 receptor antagonism as the most valid explanation
for the atypical profile of antipsychotics. Although the atypical
antipsychotic amisulpride is a highly selective D2/D3 receptor
antagonist, it has been shown that amisulpride is clearly associated with lower EPS symptoms and with a lower number of
drop-outs due to adverse events than conventional antipsychotics [7].
Therefore, our results are in line with the previous findings of a
good tolerability of amisulpride. The underlying psychopharmacological mechanism of a low profile of side effects with amisulpride is therefore not due to the combined 5HT2/D2 antagonism
as might be the case for other atypical antipsychotics [25]. Given
the fact that amisulpride lacks 5-HT2A antagonism, the pharmacological explanation of the clinically well-proven atypicality of
amisulpride is of great interest.
Clinical response
Clinical improvement and therefore efficacy especially in schizophrenia includes a large range of clinical and neurocognitive
items [27]. In our design reduction of psychopathological items
were in the focus. Clinical response was defined as a 30 % reduction from baseline in the scores of the psychopathological scales
applied. This was evaluated for both, the PANSS positive subscale and the SANS. The response quote after 2 weeks of steady
state treatment was 62.1 % for the PANSS positive subscale,
showing treatment to be effective. The SANS scale showed a
response rate of 31 % already within the first 2 weeks.
The efficacy of amisulpride was demonstrated by studies comparing the efficacy of amisulpride with that of haloperidol and
risperidone [10]. Amisulpride was at least as effective as
haloperidol and risperidone in the improvement of positive
symptoms, and significantly more efficacious than haloperidol
in reducing PANSS negative subscores (P = 0.038) in patients
with acute exacerbations. Amisulpride demonstrated a greater
improvement in BPRS total scores and PANSS negative subscores
than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations. In conclusion, amisulpride can thus be considered for use as first-line treatment
of acute and chronic schizophrenia [10]. Additionally, recently
Assion et al. [26] showed the beneficial effect of augmented
amisulpride at a daily dose of 600 mg in patients suffering from
chronic schizophrenia and treated by clozapine. Amisulpride
was more beneficial in a higher than a lower dosages and no
severe side-effects occurred. Augmented amisulpride improved
the global outcome of patients suffering from chronic schizophrenia in this pilot study and tended to be a helpful treatment
option in cases of partial or non-responsiveness to clozapine.
The correlation between clinical response and striatal D2 occupancy rate was evaluated.
It is of great interest to investigate how antipsychotic action at a
clinical level is correlated to striatal and extrastriatal D2 occupancy rate. Our short intervention study over 14 days was
designed carefully with a prospective and steady state treatment
for each patient and a strict monotherapeutic regime of amisulpride. The responder criterion with a 30 % reduction of psychopathological scores is quite well accepted. Our open trial revealed
no differences between the subgroups of responders and nonresponders regarding striatal D2 occupancy.
Up to now, there are very few investigations regarding the correlation of the clinical response and striatal occupancy. However, the general question of how to define remission criteria in
schizophrenia is still a large matter of debate [1]. On the other
hand, it has to be borne in mind that open trials are limited
regarding statements of clinical response.
The relationship between D2 occupancy and clinical response
was demonstrated by Nordström in a placebo-controlled, double-blind PET trial with the classical neuroleptic raclopride over
2 weeks. The finding was a statistically significant relationship
between D2 receptor occupancy and the antipsychotic effect of
raclopride compared to placebo [14]. The double-blind PET study
by Kapur and colleagues detected a relationship between D2
occupancy and improvement of CGI ratings, however the relationships between D2 occupancy and improvement of PANSS
and SANS scores did not achieve significance [5].
In an open trial, Pilowsky and collegues used IBZM SPET to
investigate if the striatal D2 occupancy determines response to
typical neuroleptics [16]. Their findings suggested that nonresponse to classical antipsychotic medication was not accounted
for by different striatal D2 occupancy rates. Although speculative, our results may therefore indicate a different antipsychotic
action besides the striatal D2 occupancy rate, as it is hypothesized by the concept of the limbic selectivity of amisulpride.
However, it has to be noted that the ligand 123I-IBZM does not
provide information on the extrastriatal regions (Tauscher et al.
2002).
In summary, the study results confirm that amisulpride is an
atypical neuroleptic agent with good efficacy, and good EPS tolerability despite a marked striatal D2 occupancy of 73.3 %. However, the open study design is beyond question a major limitation.
The strength of the study is the strict, wide and prospective
design with a large range of monotherapeutic steady state treatment dosages of amisulpride over 14 days and a large sample
size.
Acknowledgements
&
The investigation was supported by Sanofi-Aventis, Berlin.
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