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 (BD) is 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 at 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 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% C.I. = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared to dipyridamole and placebo (p=0.008). 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<0.001). 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 allopurinol compared with standard mood-stabilizers in mania and maintenance are warranted.

The Role of the Guanine-Based Purinergic System in Seizures and Epilepsy

“…For example, we have demonstrated that allopurinol, a xanthine oxidase inhibitor, was an effective and well-tolerated adjuvant treatment for poorly responsive schizophrenia, refractory aggressive behavior and mania [125][126][127][128][129]. These results were confirmed by an independent group [130,131] and are hypothesized to be due to an indirect increase in extracellular purine levels (adenosine and guanosine) [12].…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

“…Two RCTs have now demonstrated the efficacy of adjunctive allopurinol for the treatment of acute mania (level 1) (70,71). In an eight-week RCT, allopurinol as adjunct to lithium plus haloperidol was found to be significantly more effective than placebo in 82 patients hospitalized with acute mania (70).…”

“…In an eight-week RCT, allopurinol as adjunct to lithium plus haloperidol was found to be significantly more effective than placebo in 82 patients hospitalized with acute mania (70). In the second RCT (n = 180), comparing the addition of allopurinol, dipyridamole, or placebo to lithium for four weeks, allopurinol led to significantly greater improvements in mania scores and remission rates versus placebo (71). Although there is level 1 evidence for the use of allopurinol, given that it can cause hepatomegaly as well as hypersensitivity reactions such as Steven-Johnson syndrome and toxic epidermal necrolysis, it is recommended only for those patients that are refractory to other first-, second, and third-line treatments.…”

Marcadores periféricos e a fisiopatologia do transtorno bipolar

“…A noção de suplementar o tratamento convencional com substân-cias que aliviem a sobrecarga oxidativa no transtorno bipolar é interessante e já foi investigada em ensaios clínicos 80,81 . A N-acetilcisteína (NAC) tem se mostrado um composto interessante nesse sentido.…”