CURRENT MEDICAL RESEARCH AND OPINION®

Vol. 18, Suppl. 3, 2002, s18–22 10.1185/030079902125001083

© 2002 LIBRAPHARM LIMITED

Amisulpride: Progress and

Outcomes
Y. Lecrubier
The French Institute of Health and Medical Research, Hôpital La
Salpêtrière, Pavillon Clérambault, Paris, France

Address for correspondence: Professor Y. Lecrubier, The French Institute of Health

and Medical Research, INSERM - Unité 302, Hôpital La Salpêtrière, Pavillon
Clérambault, 47, Boulevard de l’Hôpital, 75651 Paris Cedex, France
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Keywords: Schizophrenia – Antipsychotic – Amisulpride – Haloperidol – Risperidone –

Positive symptoms – Negative symptoms – Quality of life

SUMMARY

Amisulpride is a unique atypical antipsychotic determined by PANSS negative subscale

that selectively blocks D2 and D3 receptors compared with risperidone; and similar levels
5
presynaptically in the frontal cortex, possibly of EPS .
For personal use only.

enhancing dopaminergic transmission, and Amisulpride uniquely benefits patients with

postsynaptically in the limbic areas, possibly negative symptoms and is the only
1–3
reducing it . Thus dopaminergic over-activity antipsychotic to demonstrate efficacy in
in the frontal cortex, and under-activity in the patients with predominantly negative
6–8
limbic areas, can be treated simultaneously, symptoms . Amisulpride maintains its
alleviating both positive and negative efficacy when used for medium/long-term
symptoms of schizophrenia, respectively. treatment as demonstrated in studies of up to
9,10
In acute schizophrenia, amisulpride is at 12 months . Amisulpride demonstrates
least as effective as haloperidol, with a greater greater improvement in controlling symptoms
number of patients responding to treatment as compared to haloperidol. In terms of the
determined by Clinical Global Impression (CGI) relevance of the effects, a superiority is
4
scores ( p = 0.014) . In addition, amisulpride observed for quality of life, social adaptation
is associated with a lower incidence of and functioning as measured by the Quality of
extrapyramidal symptoms (EPS) as determined Life Scale (QLS), Clinical Glocal Impression
by Simpson–Angus scores (SAS) when scale (CGI) and Functional Status
4 11
compared with haloperidol ( p = 0.0053) . Questionnaire (FSQ) scales . Amisulpride also
Amisulpride showed similar efficacy to has one of the lowest potentials of all the
12
risperidone as determined by the Brief antipsychotic agents for weight gain . The
Psychiatric Rating Scale (BPRS) and the clinical evidence for amisulpride supports its
Positive and Negative Symptom Score (PANSS) earlier pre-clinical potential, showing it to be
positive subscale; a trend towards greater an atypical antipsychotic agent with specific
improvement of negative symptoms as clinical advantages.

Introduction mission in the frontal cortex and reduces it in the

limbic areas1,3. Since dopaminergic under-activity in
What makes amisulpride unique as an atypical the frontal cortex is thought to be related to negative
antipsychotic agent is its high selectivity for symptoms, and over-activity in the limbic system is
presynaptic D2/D3 receptors in the frontal cortex, believed to be related to positive symptoms,
and for postsynaptic D2/D3 receptors in subcortical amisulpride should present with a broad spectrum
limbic areas. Thus, it facilitates dopaminergic trans- pharmacological profile. In addition, the interaction

s18 Paper 2289

 with striatal D2 receptors is very low reducing the CGI %: very much / much improved
likelihood of extrapyramidal symptoms (EPS). 100%
p = 0.014

Unlike other atypical antipsychotics, amisulpride has

minimal affinity for 5HT2, muscarinic, α1 adrenergic 62
or histaminergic H1 receptors1,3. This is in favour of a
44
low incidence of other side-effects. 50

This paper reviews recent clinical evidence dem-

onstrating the effectiveness of amisulpride in treating
the symptomatology of schizophrenia. In partic-
0
ular, amisulpride is compared with the classical Amisulpride 800 mg Haloperidol 20 mg
(n = 94) (n = 94)
antipsychotic, haloperidol, and another atypical,
risperidone, in both short- and medium/long-term
studies. Figure 1. Responder rates of amisulpride versus
haloperidol. A multicentre, double-blind trial of schizo-
phrenia patients (n = 191) with acute exacerbations
randomised to amisulpride (n = 95) or haloperidol
Efficacy of Amisulpride in (n = 96) for 6 weeks. CGI, Clinical Global Impression.
Patients with Positive Reproduced with permission from Möller et al., 19974
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Symptoms
risperidone in terms of the percentage of responders,
The first priority in acutely psychotic patients is to defined as patients who improved by 50% or more, on
reduce positive symptoms. Amisulpride is at least as both the PANSS ( p < 0.036) and BPRS ( p < 0.02)
effective as reference drugs, such as haloperidol (clas- scales. The criterion of 50% improvement was more
sical) and risperidone (atypical), in the treatment of rigorous and realistic than the commonly used 20%,
positive symptoms. which makes this result even more impressive.
There was also a significant difference in favour of
amisulpride in the percentage of those who were
Amisulpride versus Haloperidol
For personal use only.

‘very much’ or ‘much improved’ on the CGI Scale

Patients treated with amisulpride showed similar ( p < 0.042)13,14. This suggested that the overall ther-
improvements in symptomatology to patients treated apeutic ratio was good and clinically relevant.
with haloperidol, as assessed on the Brief Psychiatric
Rating Scale (BPRS)4. Treatment with amisulpride
Efficacy of Amisulpride in Patients with
resulted in a significantly greater number of respond-
Negative Symptoms
ers than haloperidol ( p = 0.014), as demonstrated on
the Clinical Global Impression (CGI) scale (Figure 1). Treatment with amisulpride is associated with
significant improvements in negative symptoms
compared with placebo or other antipsychotics4,6,8,9.
Amisulpride versus Risperidone
Amisulpride produced significant improvements in
Amisulpride has been shown to be at least as effective negative symptoms compared with placebo
as risperidone in short and longer term studies5,13. A ( p < 0.02) over a 6-week period, when assessed on
recent clinical study comparing amisulpride (initially the Scale for the Assessment of Negative Symptoms
600 mg/day, then adjusted) with risperidone (6 mg/ (SANS) 6. In another medium/long-term study,
day, then adjusted) was conducted (The Amisulpride amisulpride produced significant reductions on the
Risperidone Study – AMIRIS). A total of 310 full range of negative symptoms, as assessed using
patients were followed for six months with a possible SANS9 (Figure 3). The effect of amisulpride on nega-
extension to one year. Just over 75% of the tive symptoms is maintained in all domains, in this
amisulpride-treated patients were of the paranoid case improving affective flattening, alogia, avolition/
type, compared with 70% of the patients treated with apathy, anhedonia/asociality, and attention impair-
risperidone. After 6 months, amisulpride was shown ment.
to be at least as effective as risperidone as determined
by the total of the PANSS scores14. There were no
significant differences for the other scales and Long-term Efficacy of
subscales, indicating that amisulpride generally shows Amisulpride
at least the same efficacy as risperidone (Figure 2).
In terms of the relevance of the global therapeutic Amisulpride and haloperidol were compared in a
effect, after six months, there was a statistically sig- 12-month, open-label, randomised, multicentre
nificant advantage for amisulpride compared with trial10. The improvement in positive symptoms,

Amisulpride: Progress and Outcomes Lecrubier s19

 M6 – D0

PANSS PANSS PANSS

total positive negative BPRS SANS

Efficacy measure score

-5
ns
-10
-15 ns
ns
-20 ns
-25
-30
-35 *p < 0.001
Amisulpride Risperidone

*p non-inferiority
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Figure 2. Medium-term efficacy of amisulpride versus risperidone. A double-blind, randomised, parallel-group study
of 310 patients treated with amisulpride (n = 152; 600 mg/day then adjusted) and risperidone (n = 158; 6 mg/day
then adjusted). Efficacy measures included Positive and Negative Symptom Scale (PANSS), Brief Psychiatric Rating
Scale (BPRS), and the Scale for the Assessment of Negative Symptoms (SANS)14

Mean change of SANS subscores between D0 and Dend (ITT)

%
60 p < 0.0002
p < 0.0002 p < 0.02
50 p < 0.0007
For personal use only.

40 p < 0.005
30

20

10

0
Affective Alogia Avolition Anhedonia Attention
flattening apathy asociality impairment

Amisulpride 100 mg (n = 69) Placebo (n = 71)

Figure 3. Amisulpride efficacy after 6 months in patients with predominantly negative symptoms. A multicentre,
parallel-group, double-blind, placebo-controlled study of 141 patients were randomised to amisulpride (n = 69)
100 mg/day or placebo (n = 72) for 6 months. All patients met DSM-III, two of Andreason’s criteria for negative
components of schizophrenia, a score of ≥60 on SANS and £50 on SAPS. Data were analysed on intent-to-treat basis.
Reproduced with permission from Loo et al., 1997 9

assessed on BPRS score, was significantly greater in improvement of negative symptoms between
the amisulpride group than in the haloperidol group amisulpride and haloperidol was even greater than
( p = 0.047) throughout the course of the study (Fig- the difference in positive symptom scores, suggesting
ure 4a). Most of the improvement occurred within a qualitative difference with respect to the two com-
the first month, and efficacy was maintained for the pounds in terms of negative symptoms.
duration of the study. This superiority of amisulpride
over haloperidol may be associated with signifi-
cantly fewer withdrawals due to lack of efficacy Tolerability
( p = 0.009) (Figure 4b).
Amisulpride also showed a significantly greater Several studies have found that amisulpride and
improvement in the negative symptom score on risperidone are better tolerated than haloperidol with
the PANSS scale compared with haloperidol regard to extrapyramidal symptoms (EPS)4,10,11,15.
( p = 0.0001) (Figure 4c). The difference in the Weight gain was also shown to be significantly greater

s20 Amisulpride: Progress and Outcomes Lecrubier

 BPRS total score per visit
60

55

BPRS total score

50
Haloperidol (n = 117)
5–20 mg
45
p = 0.047
40
Amisulpride (n = 366)
200–800 mg
35

D0 D30 D90 D180 D270 D360

(a) Time (days)

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Drop-out rate due to lack of efficacy/lost to follow-up

p = 0.009
30

22
Percentage of patients

20

12
10
For personal use only.

0
Amisulpride 200–800 mg Haloperidol 5–20 mg
(b) (n = 327) (n = 93)

PANSS negative subscore per visit

25
PANSS negative subscore

Haloperidol (n = 117)
5–20 mg

20 p = 0.0001

Amisulpride (n = 366)
200–800 mg

15

D0 D30 D90 D180 D270 D360

(c) Time (days)

Figure 4. Long-term efficacy of amisulpride. A multicentre, parallel-group, randomised, open-label trial of patients
(n = 489) with chronic or subchronic schizophrenia were treated with amisulpride 200–800 mg/day (n=370) or
haloperidol 5–20 mg/day (n = 119) for 12 months. (a) Improvement of positive symptomatology on the Brief
Psychiatric Rating Scale (BPRS); (b) Drop-out rates; (c) Improvement of negative symptomatology on the PANSS
negative subscale. Reproduced with permission from Colonna et al., 200010.

Amisulpride: Progress and Outcomes Lecrubier s21

 Mean change from baseline
p = 0.026*

1.4
1.5

kg 1.0

0.4
0.5

0
Amisulpride 800 mg (n = 114) Risperidone 8 mg (n = 110)

*p within the amisulpride group: NS; p within the risperidone group: 0.0004
Data confirmed in AMIRIS Study (0.6 vs 1.4; p < 0.03)
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Figure 5. Effect of amisulpride versus risperidone on weight gain. A multi-centre, parallel-group, double-blind trial of 228
patients with acute exacerbations of schizophrenia. After a 3–6 day washout, patients were randomised to amisulpride 800 mg/
day (n = 115) or risperidone 8 mg/day (n = 113). Reproduced with permission from Peuskens et al., 19995

with risperidone than with amisulpride (1.4 vs. 3. Perrault GH, Depoortere R, Morel E, Sanger DJ, Scatton
B. Psychopharmacological profile of amisulpride: an
0.4 kg, p = 0.026)5 (Figure 5). This observation was antipsychotic drug with presynaptic D2/D3 dopamine
confirmed in the AMIRIS study at eight weeks (1.4 receptor antagonistic activity and limbic selectivity. J
Pharmacol Exp Ther 1997;280:73-82
vs. 0.6 kg, p < 0.03) 13. 4. Möller HJ, Boyer P, Fleurot O, Rein W. Improvement of
acute exacerbations of schizophrenia with amisulpride: a
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comparison with haloperidol. Psychopharmacology 1997;

132:396-401
Conclusions 5. Peuskens J, Bech P, Möller HJ, Bale R, Fleurot O, Rein W.
Amisulpride versus risperidone in the treatment of acute
As would be predicted from the pharmacological pro- exacerbations of schizophrenia. Psychiatry Res 1999;88:
107-17
file of a pure D2/D3 receptor blocker, amisulpride is 6. Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F.
an atypical antipsychotic agent, effective on positive Treatment of negative symptoms in schizophrenia with
amisulpride. Br J Psychiatry 1995;166:68-72
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s22 Amisulpride: Progress and Outcomes Lecrubier