Amisulpride plus valproate vs haloperidol plus valproate in the treatment of acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial

Figures & data

Figure 1 Subject flow diagram.

Abbreviations: ITT, intention to treat; PP, per protocol.

Table 1 Major protocol violations and premature study discontinuations in the ITT population. Note that individual subjects may present more than one protocol violation or reason for discontinuation and the categories are thus not mutually exclusive

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 58)
Major protocol violations	15	3
Week 3 visit time window not respected	3	0
Week 12 visit time window not respected	7	2
No BPRS data at baseline	–	1
No GAS data at baseline	–	1
Use of prohibited psychotropic medication (psychotropic agents other than hypnotics and benzodiazepines ≥72 hours)	6	0
Premature treatment discontinuations	15	23
Occurrence of an adverse event	7	15
Perceived lack of efficacy	4	5
Consent withdrawn	3	6
Poor compliance	1	1
Other	1	2

Abbreviations: BPRS, Brief Psychiatric Rating Scale GAS, Global Assessment Scale.

Table 2 Baseline demographic and clinical characteristics of subjects in the intention to treat population. Data for categorical variables are presented as numbers of subjects (%) and quantitative variables as mean ± standard deviation

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 58)
Gender (female)	36 (58.1%)	35 (60.3%)
Age (years)	41.8 ± 12.9	45.4 ± 12.3
Body mass index (kg/m^2)	26.3 ± 5.4	26.0 ± 4.9
Duration of bipolar disorder (years)	12.2 ± 8.9	13.0 ± 8.8
Nr of previous episodes	7.2 ± 8.6	6.2 ± 5.5
Nr of previous manic episodes	3.8 ± 5.0	4.5 ± 4.7
Time since last episode (years)	1.8 ± 1.8	1.8 ± 2.1
Type of the last episode
Manic episode	41 (66.1%)	43 (74.1%)
Hypomanic episode	1 (1.6%)	1 (1.7%)
Mixed episode	2 (3.2%)	1 (1.7%)
Major depressed episode	18 (29.0%)	13 (22.4%)
Psychiatric comorbidity	9 (14.5%)	9 (15.5%)
Past psychotropic drug usea	54 (87.1%)	51 (87.9%)
Previous hospitalization	51 (82.3%)	54 (93.1%)
Mood state at inclusion into study
Dysphoric mania	3 (4.8%)	14 (24.1%)
Euphoric mania	59 (95.2%)	44 (75.9%)
YMRS score	29.2 ± 5.2	30.5 ± 5.3
BPRS score	35.8 ± 9.4	37.7 ± 9.9
GAS score	43.5 ± 10.0	43.8 ± 11.2
MADRS score	8.7 ± 3.1	9.4 ± 3.7
CGI-BP Severity score
Mania	5.3 ± 0.5	5.4 ± 0.5
Depression	1.2 ± 0.8	1.2 ± 0.6
General bipolar	4.8 ± 1.0	5.2 ± 0.9

a In previous 6 months.

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI-BP, Clinical Global Impression Bipolar Sale; GAS, Global Assessment Scale; MADRS, Montgomery and Åsberg Depression Rating Scale; YMRS, Young Mania Rating Scale.

Figure 2 Treatment dose at study end. Left: amisulpride; right: haloperidol.

Figure 3 Young Mania Rating Scale scores over the course of the study in the intention to treat population. Data are presented as mean scores ± standard deviation. ○: amisulpride group; ■: haloperidol group.

Table 3 Changes in rating scale scores over the study period in the ITT population. Data are presented as mean values ± standard deviation of change from baseline

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 58)	p (ANCOVA)
YMRS score (mean change)
Week 3	−20.5 ± 8.4	−22.2 ± 9.1	0.671 (NS)
Week 12	−23.0 ± 10.4	−25.6 ± 9.3	0.309 (NS)
BPRS score (mean change)
Week 3	−11.3 ± 8.7	−13.7 ± 9.3	0.312 (NS)
Week 12	−12.0 ± 11.1	−13.9 ± 10.4	0.694 (NS)
GAS score (mean change)
Week 12	34.2 ± 20.2	31.1 ± 21.1	0.420 (NS)
MADRS score (mean change)
Week 12	−3.2 ± 8.1	−1.1 ± 9.9	0.094 (NS)
CGI-BP score (mean change)
Mania	−3.6 ± 1.3	−3.8 ± 1.2	0.318 (NS)
Depression	0.3 ± 1.2	0.5 ± 1.3	0.269 (NS)
General bipolar	−2.6 ± 1.8	−3.0 ± 1.8	0.230 (NS)

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI-BP, Clinical Global Impression Bipolar Sale; GAS, Global Assessment Scale; MADRS, Montgomery and Åsberg Depression Rating Scale; YMRS, Young Mania Rating Scale; NS, nonsignificant.

Figure 4 Improvement over the course of the study in the intention to treat population. Patient satisfaction questionnaire. Grey bars: much improved; black bars: very much improved.

Table 4 Treatment-emergent adverse events reported in the Safety populationa

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 59)	P
TEAEs	41 (66.1%)	51 (86.4%)	0.009
TEAEs related to study treatment	34 (54.8%)	48 (81.4%)	0.002
Severe TEAEs	2 (3.2%)	12 (20.3%)	0.004
Severe TEAEs related to study treatment	None	12 (20.3%)	<0.001
TEAEs resulting in discontinuation	7 (11.3%)	15 (25.4%)	0.044
Serious TEAEs	3 (4.8%)	5 (8.5%)	0.484 (NS)
Serious TEAEs related to study treatment	None	4 (6.8%)	0.054 (NS)

a Data are presented as number of subjects (%).

Abbreviations: TEAEs, treatment-emergent adverse events; NS, nonsignificant.

Table 5 Measures of extrapyramidal function in the Safety populationa

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 59)	P
Simpson-Angus Scale
Baseline	0.4 (0.17; 0.70)	1.1 (0.33; 1.94)	0.001 (ANOVA)
Endpoint	1.6 (0.86; 2.35)	4.8 (3.37; 6.26)
Change	1.2 (0.46; 1.87)	3.7 (2.38; 4.98)
Barnes Akathisia Index
Baseline	0.0 (−0.01; 0.10)	0.2 (0.05; 0.32)	<0.001 (t-test)
Endpoint	0.1 (0.01; 0.25)	0.7 (0.44; 1.02)
AIMS score
Baseline	0.3 (0.04; 0.63)	1.0 (0.29; 1.68)	0.035 (ANOVA)
Endpoint	0.2 (0.01; 0.41)	1.8 (0.61; 2.93)
Change	−0.1 (−0.35; 0.09)	0.8 (−0.08; 1.62)
Use of antiparkinsonian medication	12 (19.4%)	32 (54.2%)	0.001 (χ^2 test)

a Data are presented as mean values with 95% confidence intervals.

Abbreviation: AIMS, Abnormal Involuntary Movement Scale.

Table 6 Potentially clinically significant abnormalities in biochemical parameters in the Safety population

	Amisulpride + valproate (N = 62)	Haloperidol + valproate (N = 59)
Aspartate aminotransferase >2 × ULN	–	1
Alanine aminotransferase >2 × ULN	1	2
γ-Glutamyltransferase >2 × ULN	2	3
Alkaline phosphatase >1.5 × ULN	–	1
Potassium <3 mmol/L or ≥5.5 mmol/L	–	1
Total bilirubin >ULN	10	3
Conjugated bilirubin >ULN	8	4

Abbreviation: ULN, upper limit of normal.