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
J Clin Psychiatry 2008;69(8):1237-1245
© Copyright 2016 Physicians Postgraduate Press, Inc.
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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
allopurinol compared with standard mood stabilizers
in mania and maintenance are warranted.
Trial Registration: clinicaltrials.gov