title: A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania.
abstract: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00560079.
authors.affiliation: Bipolar Disorder Research Program, Espirita Hospital of Porto Alegre, Porto Alegre, RS, Brazil. machadovieirar@terra.com.br
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Jair C
authors.initials: JC
authors.lastname: Soares
authors.forename: Diogo R
authors.initials: DR
authors.lastname: Lara
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: João V
authors.initials: JV
authors.lastname: Busnello
authors.forename: Getulio
authors.initials: G
authors.lastname: Marca
authors.forename: Angelo
authors.initials: A
authors.lastname: Cunha
authors.forename: Diogo O
authors.initials: DO
authors.lastname: Souza
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Flavio
authors.initials: F
authors.lastname: Kapczinski
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000493:Allopurinol / Q000009:adverse effects* / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000534:rehabilitation; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004176:Dipyridamole / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006760:Hospitalization; D006801:Humans; D016651:Lithium Carbonate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires
chemical_list: D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D016651:Lithium Carbonate; D000493:Allopurinol; D004176:Dipyridamole