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Allopurinol augmentation in the outpatient treatment of bipolar mania: a pilot study


  • Clinical Trials Registration: A double-blind, placebo-controlled augmentation study with allopurinol for treatment resistant mania, identifier: NCT00643123.

Corresponding author:
Alexander Fan, M.D.
Department of Psychiatry and Behavioral Neurosciences
Cedars-Sinai Medical Center
8730 Alden Drive, Room C301
Los Angeles, CA 90048
Fax: 310-423-8397


Fan A, Berg A, Bresee C, Glassman LH, Rapaport MH. Allopurinol augmentation in the outpatient treatment of bipolar mania: a pilot study. Bipolar Disord 2012: 14: 206–210. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.

Background:  Allopurinol promotes the salvage of purines, possibly increasing endogenous adenosine levels. Recent studies suggest that adenosine has neuroprotective and inhibitory effects. Two previous inpatient trials demonstrated that allopurinol has anti-manic activity. Our objective was to test allopurinol as an adjunct to standard medications in bipolar disorder manic outpatients.

Methods:  In this double-blind, placebo-controlled trial, 27 subjects who met DSM-IV criteria for bipolar disorder and scored ≥ 14 on the Young Mania Rating Scale (YMRS) were randomized to augmentation with allopurinol or placebo for six weeks. The primary efficacy measure was the YMRS. The primary safety measure was the Treatment Emergent Symptom Scale.

Results:  The effect of allopurinol augmentation in decreasing mean YMRS scores was modest, with an overall effect size of −0.25 (Cohen’s d). Allopurinol-treated individuals who abstained from caffeine (n = 4) had a greater decrease in YMRS scores (−15.3 ± 1.8) than subjects using caffeine (n = 5) (−9.6 ± 3.4, p = 0.219), with an effect size of −0.86.

Conclusion:  In this small outpatient pilot study, allopurinol augmentation did not show a statistically significant improvement over placebo in attenuating manic symptoms. Subjects with restricted caffeine use showed a greater effect size compared to caffeine users. This finding may be interpreted as corroborating the hypothesized mechanism of action of allopurinol’s anti-manic effect in previous studies.