Skip to main content Accessibility help
×
Home

Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials

  • Francesco Bartoli (a1), Cristina Crocamo (a1), Massimo Clerici (a1) and Giuseppe Carrà (a2)

Abstract

Background

Since bipolar disorder seems to be associated with purinergic system dysfunction, allopurinol might be effective in treating symptoms of mania.

Aims

To estimate the efficacy and tolerability of allopurinol as adjunctive treatment for mania symptoms in people with bipolar affective disorder.

Method

We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the effects of adjunctive allopurinol and placebo on mania symptom changes.

Results

Five RCTs were included in the meta-analysis. Participants with allopurinol augmentation had a significantly greater decrease in mania symptoms than those with placebo (SMD= −0.34, P = 0.007), especially in people with the most severe forms of mania. Remission rates, although based on only two studies (n = 177), were significantly higher among individuals receiving allopurinol, whereas for discontinuation and side-effects no difference was found.

Conclusions

Our finding of a small to moderate effect size and overall low evidence for add-on allopurinol in reducing mania symptoms indicate that its use in routine practice needs further elucidation.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials
      Available formats
      ×

Copyright

Corresponding author

Dr Francesco Bartoli, Department of Medicine and Surgery, University of Milano Bicocca, Via Cadore 48, 20900 Monza (MB), Italy. Email: f.bartoli@campus.unimib.it

Footnotes

Hide All

Declaration of interest

None.

Footnotes

References

Hide All
1 Pacher, P, Nivorozhkin, A, Szabo, C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58: 87114.
2 Machado-Vieira, R, Lara, DR, Souza, DO, Kapczinski, F. Therapeutic efficacy of allopurinol in mania associated with hyperuricemia. J Clin Psychopharmacol 2001; 21: 621–2.
3 Ortiz, R, Ulrich, H, Zarate, CA, Machado-Vieira, R. Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics. Prog Neuropsychopharmacol Biol Psychiatry 2015; 57: 117–31.
4 Machado-Vieira, R, Lara, DR, Souza, DO, Kapczinski, F. Purinergic dysfunction in mania: an integrative model. Med Hypotheses 2002; 58: 297304.
5 Salvadore, G, Viale, CI, Luckenbaugh, DA, Zanatto, VC, Portela, LV, Souza, DO, et al Increased uric acid levels in drug-naïve subjects with bipolar disorder during a first manic episode. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 819–21.
6 Albert, U, De Cori, D, Aguglia, A, Barbaro, F, Bogetto, F, Maina, G. Increased uric acid levels in bipolar disorder subjects during different phases of illness. J Affect Disord 2015; 173: 170–5.
7 De Berardis, D, Conti, CM, Campanella, D, Carano, A, Di Giuseppe, B, Valchera, A, et al Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder. J Biol Regul Homeost Agents 2008; 22: 195200.
8 Muti, M, Del Grande, C, Musetti, L, Marazziti, D, Turri, M, Cirronis, M, et al Serum uric acid levels and different phases of illness in bipolar I patients treated with lithium. Psychiatry Res 2015; 225: 604–8.
9 Kesebir, S, Tatldil Yaylac, E, Suner, O, Gultekin, BK. Uric acid levels may be a biological marker for the differentiation of unipolar and bipolar disorder: the role of affective temperament. J Affect Disord 2014; 165: 131–4.
10 Alda, M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry 2015; 20: 661–70.
11 Shorter, E. The history of lithium therapy. Bipolar Disord 2009; 11 (suppl 2): 49.
12 Hirota, T, Kishi, T. Adenosine hypothesis in schizophrenia and bipolar disorder: a systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators. Schizophr Res 2013; 149: 8895.
13 Jahangard, L, Soroush, S, Haghighi, M, Ghaleiha, A, Bajoghli, H, Holsboer-Trachsler, E, et al In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. Eur Neuropsychopharmacol 2014; 24: 1210–21.
14 Weiser, M, Burshtein, S, Gershon, AA, Marian, G, Vlad, N, Grecu, IG, et al Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Bipolar Disord 2014; 16: 441–7.
15 Sanches, M, Newberg, AR, Soares, JC. Emerging drugs for bipolar disorder. Expert Opin Emerg Drugs 2010; 15: 453–66.
16 Zarate, CA, Manji, HK. Putative drugs and targets for bipolar disorder. Mt Sinai J Med 2008; 75: 226–47.
17 Moher, D, Liberati, A, Tetzlaff, J, Altman, DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009; 6: e1000097.
18 Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–35.
19 Schunemann, HJ, Oxman, AD, Vist, GE, Higgins, JP, Deeks, JJ, Glasziou, P, et al Interpreting results and drawing conclusions. In Cochrane Handbook for Systematic Reviews of Interventions (eds Higgins, JP, Green, S). Cochrane Collaboration, 2008.
20 Higgins, JP, Altman, DG, Gotzsche, PC, Juni, P, Moher, D, Oxman, AD, et al The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.
21 Dumville, JC, Torgerson, DJ, Hewitt, CE. Reporting attrition in randomised controlled trials. BMJ 2006; 332: 969–71.
22 Gupta, SK. Intention-to-treat concept: a review. Perspect Clin Res 2011; 2: 109–12.
23 Deeks, JJ, Higgins, JP, Altman, DG. Analysing data and undertaking meta-analyses. In Cochrane Handbook for Systematic Reviews of Interventions (eds Higgins, JP, Green, S). Cochrane Collaboration, 2008.
24 Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60.
25 Sterne, JA, Egger, M, Moher, D. Addressing reporting biases. In Cochrane Handbook for Systematic Reviews of Interventions (eds Higgins, JP, Green, S). Cochrane Collaboration, 2008.
26 Akhondzadeh, S, Milajerdi, MR, Amini, H, Tehrani-Doost, M. Allopurinol as an adjunct to lithium and haloperidol for treatment of patients with acute mania: a double-blind, randomized, placebo-controlled trial. Bipolar Disord 2006; 8: 485–9.
27 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: 206–10.
28 Machado-Vieira, R, Soares, JC, Lara, DR, Luckenbaugh, DA, Busnello, JV, Marca, G, et al 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: 1237–45.
29 Cohen, J. Statistical Power Analysis for the Behavioral Sciences (2nd edn). Erlbaum, 1988.
30 Seth, R, Kydd, AS, Buchbinder, R, Bombardier, C, Edwards, CJ. Allopurinol for chronic gout. Cochrane Database Syst Rev 2014; 10: CD006077.
31 Ketter, TA, Nasrallah, HA, Fagiolini, A. Mood stabilizers and atypical antipsychotics: bimodal treatments for bipolar disorder. Psychopharmacol Bull 2006; 39: 120–46.
32 Bartoli, F, Crocamo, C, Gennaro, GM, Castagna, G, Trotta, G, Clerici, M, et al Exploring the association between bipolar disorder and uric acid: a mediation analysis. J Psychosom Res 2016; 84: 56–9.
Type Description Title
PDF
Supplementary materials

Bartoli et al. supplementary material
Supplementary Material

 PDF (143 KB)
143 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Allopurinol as add-on treatment for mania symptoms in bipolar disorder: Systematic review and meta-analysis of randomised controlled trials

  • Francesco Bartoli (a1), Cristina Crocamo (a1), Massimo Clerici (a1) and Giuseppe Carrà (a2)
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *