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

Abstract

The primary objective of this study was to compare the effectiveness of combination treatment of valproate and amisulpride with that of valproate and haloperidol in bipolar I disorder. Adult inpatients with a current manic episode fulfilling DSM-IV-TR diagnostic criteria for bipolar type I disorder were included. Patients were randomized to amisulpride (400–800 mg/day) or haloperidol (5–15 mg/day) for 3 months and all received valproate. The primary effectiveness criterion was the percentage of responders (defined by a decrease of ≥50% of the Y-MRS) in patients completing the study. Safety was evaluated by adverse event reporting, determination of extrapyramidal function and clinical examination. Sixty-two patients were randomized to receive valproate-amisulpride, and 61 to receive valproate-haloperidol. At study end, responder rates were 72.6% in the amisulpride group and 65.5% in the haloperidol group. Remission rates were 83.9% and 89.7%, respectively. At study end, neither response rates nor remission rates differed significantly between groups. Treatment-emergent adverse events occurred significantly (p = 0.009) more frequently in the haloperidol group (86.4%) than in the amisulpride group (66.1%). In conclusion, the valproate–amisulpride combination was as effective as the valproate – haloperidol combination in bipolar I patients, with a better safety profile.

Keywords:

• amisulpride
• valproate
• haloperidol
• clinical trial
• mania
• bipolar disorder

Acknowledgements

The authors wish to thank the principal investigators of all participating study centers and their teams for their enthusiastic contribution to this project:

Czech Republic: Dr J Tomanova (Brno-Bohunice); Dr L Hosak (Hradec Králové); Dr D Seifertova (Praha 8 – 1); Dr T Petranova (Plzen-Lochotín); Dr J Boucek (Olomouc); Dr V Hanuskova (Opava); Dr P Navratil (Praha 6); Dr V Burian (Tabor); Dr L Macak (Tabor). France: Pr P Thomas (Lille); Dr G Ruetsch (Poitiers); Dr J-A Meynard (La Rochelle); Dr M Cazenave (Bordeaux); Dr J Louvrier (Bully Les Mines); Dr GP Badet (Dijon); Dr M Abbar (Nîmes); Dr J-C Samuelian (Marseille); Dr J Palazzolo (Nice); Dr B Millet (Rennes); Dr G Allio (Sotteville Les Rouen). Poland: Dr I Krupka Matuszczyk (Katowice); Dr H Marmurowska (Lublin); Dr J Landowski (Gdansk); Dr M Janiszewski (Torun); Dr A Przewlocka (Krakow); Dr J Bukowski (Gorlice). Slovakia: Dr P Cernak (Pezinok); Dr E Palova (Kosice); Dr L Nabelek (Banská Bystrica); Dr L. Vavrusova (Bratislava); Dr V Novotny (Bratislava); Dr H Shahpesandi (Liptovsky Mikulas); Dr Z Janikova (Liptovsky Mikulas); Dr M Halmo (Bratislava – Petrzalka); Dr V Garaj (Bojnice); Dr L Vircik (Michalovce). Spain: Dr MA Gonzales Torres (Bilbao); Dr E Vieta (Barcelona); Dr E Alvarez (Barcelona); Dr A Carrasco (Ciudad Real).

Disclosures

This study was sponsored and funded by Sanofi-Aventis, manufacturers of amisulpride and of sodium valproate. Operational management of the study (study monitoring, data collection, and data analysis) was delegated by ICTA PM, a contract research association.

The authors made up the Steering Committee for the trial. They advised the study sponsor on the design of the protocol and the implementation of the study, reviewed the results, made suggestions for further analyses, and participated in the interpretation of the data. Both authors received honoraria from the sponsor for their involvement in the study as well as consultancy fees for advice in the field of psychiatry in general over the previous 3 years. The corresponding author, PT, had full access to all data from the study, and had final responsibility for the decision to submit the finalized manuscript for publication.