OBJECTIVE: The therapeutics for bipolar disorders are still far from adequate, and new options with improved effectiveness, safety, and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania. METHOD: A randomized, placebo-controlled, double-blind study was performed in adult inpatients (N = 180) with a DSM-IV-TR diagnosis of bipolar I disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (N = 60), dipyridamole 200 mg/day (N = 60), or placebo (N = 60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 21, and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006. RESULTS:Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p < .001) and day 28 (p = .003) compared with placebo using a linear model analysis (d = 0.32, 95% CI = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo (p = .008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasmauric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p < .001). CONCLUSION:Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder. Further placebo-controlled studies with allo-purinol compared with standard mood stabilizers in mania and maintenance are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00560079.
RCT Entities:
OBJECTIVE: The therapeutics for bipolar disorders are still far from adequate, and new options with improved effectiveness, safety, and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania. METHOD: A randomized, placebo-controlled, double-blind study was performed in adult inpatients (N = 180) with a DSM-IV-TR diagnosis of bipolar I disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (N = 60), dipyridamole 200 mg/day (N = 60), or placebo (N = 60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 21, and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006. RESULTS:Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p < .001) and day 28 (p = .003) compared with placebo using a linear model analysis (d = 0.32, 95% CI = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo (p = .008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p < .001). CONCLUSION:Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder. Further placebo-controlled studies with allo-purinol compared with standard mood stabilizers in mania and maintenance are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00560079.
Authors: Giacomo Salvadore; Carlos I Viale; David A Luckenbaugh; Vanessa C Zanatto; Luiz V Portela; Diogo O Souza; Carlos A Zarate; Rodrigo Machado-Vieira Journal: Prog Neuropsychopharmacol Biol Psychiatry Date: 2010-03-03 Impact factor: 5.067
Authors: Konstantinos N Fountoulakis; Lakshmi Yatham; Heinz Grunze; Eduard Vieta; Allan Young; Pierre Blier; Siegfried Kasper; Hans Jurgen Moeller Journal: Int J Neuropsychopharmacol Date: 2017-02-01 Impact factor: 5.176
Authors: Susan A Masino; Masahito Kawamura; Jessica L Cote; Rebecca B Williams; David N Ruskin Journal: Neuropharmacology Date: 2012-08-24 Impact factor: 5.250
Authors: A Cheffer; A R G Castillo; J Corrêa-Velloso; M C B Gonçalves; Y Naaldijk; I C Nascimento; G Burnstock; H Ulrich Journal: Mol Psychiatry Date: 2017-09-26 Impact factor: 15.992
Authors: Rushaniya Khairova; Rohit Pawar; Giacomo Salvadore; Mario F Juruena; Rafael T de Sousa; Márcio G Soeiro-de-Souza; Mirian Salvador; Carlos A Zarate; Wagner F Gattaz; Rodrigo Machado-Vieira Journal: Mol Med Rep Date: 2011-12-22 Impact factor: 2.952
Authors: Rodrigo Machado-Vieira; David A Luckenbaugh; Marcio G Soeiro-de-Souza; Getulio Marca; Ioline D Henter; Joao V Busnello; Wagner F Gattaz; Carlos A Zarate Journal: J Affect Disord Date: 2012-08-17 Impact factor: 4.839
Authors: Daniel C Mathews; Erica M Richards; Mark J Niciu; Dawn F Ionescu; Joseph J Rasimas; Carlos A Zarate Journal: Transl Neurosci Date: 2013-06 Impact factor: 1.757