February 2009

Combination Approach to Childhood Anxiety
In a study of children with anxiety disorders, the combination of cognitive behavioral therapy and an antidepressant was superior to either treatment alone.

Antipsychotic-Induced Weight Gain: Management Without Meds
Several behavioral interventions effectively promote weight loss in patients taking antipsychotics.

Allopurinol: Novel Treatment for Mania?
Allopurinol (Lopurin and others) as an adjunct to lithium may help improve manic symptoms in patients with bipolar disorder.

In Brief
Behavioral Risk Factors Mediate Hospitalization and Mortality; International Internet Day of Action Results in Drug Seizures

Adjunctive Estrogen for Schizophrenia?
Exogenously administered estradiol added to antipsychotic therapy might benefit women with schizophrenia.

Injection Site Reactions with Naltrexone
Injections of extended-release naltrexone (Vivitrol) can cause serious skin reactions.

Allopurinol: Novel Treatment for Mania?

February 2009

Purines are components of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and also serve as neurotransmitters. Examples of purines include adenine, guanine, xanthine, theobromine, caffeine, and uric acid. As far back as the eras of Kraepelin and Cade, there have been hypotheses about a possible role for purines, especially uric acid, in mania. Recent genetic data implicate purinergic dysfunction in the pathophysiology of Bipolar Disord er and recurrent major depression.1,2

Allopurinol (Lopurin and others) is a xanthine oxidase inhibitor used to prevent gouty arthritis and nephropathy and for the treatment of secondary hyperuricemia during cancer chemotherapy. Allopurinol and dipyridamole (Persantine and others), an anti-platelet agent and vasodilator, appear to regulate brain purinergic metabolism. Allopurinol has been used as an adjunct to antipsychotic drugs in difficult cases of schizophrenia, mania, and aggression. In 2006, Akhondzadeh et al reported significant benefit in manic symptoms when they added allopurinol to a regimen of lithium plus haloperidol (Haldol and others) in an 8-week, double-blind, placebo-controlled trial.3 Since then, Machado-Vieira and coworkers in Brazil studied allopurinol and dipyridamole to augment lithium in the treatment of acute bipolar mania.4

The authors enrolled 180 male and female adult inpatients with bipolar I disorder, who were in a manic episode, with or without psychotic features. All patients took lithium, started at 600 mg/day and then titrated to achieve plasma levels of 0.6 to 1.2 mmol/L. In addition, patients were randomly assigned in double-blind fashion to receive 4 weeks of treatment with either allopurinol, 600 mg/day; dipyridamole, 200 mg/day; or placebo. Diazepam (Valium and others), up to 20 mg/day, was allowed as needed, but antipsychotic drugs were not.

Patients assigned to allopurinol showed statistically superior improvement in manic symptoms compared with those taking placebo at weeks 3 (P < .001) and 4 (P = .003), whereas the dipyridamole group showed no significant benefits compared with placebo-treated subjects. Remission rates were higher in the allopurinol group than in the other two groups (P = .008), and women had better response rates than men. Anti-manic effects of allopurinol were significantly associated with uric acid levels, suggesting a role for purinergic system dysfunction in mania. Both adjuncts were well tolerated, with no significant side effect differences among the three groups.

Allopurinol is an old agent available by prescription. It can cause severe and life-threatening hypersensitivity reactions and hepatotoxicity. Bone marrow suppression is a possibility, and it must be used with caution in patients with renal impairment. At this time, the work of Dr Machado-Vieira's group must be considered preliminary and a promising lead but not yet ready for "prime time."

1Barden N, Harvey M, Gagné B, Shink E, Tremblay M, Raymond C, Labbé M, Villeneuve A, Rochette D, Bordeleau L, Stadler H, Holsboer F, Müller-Myhsok B: Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 2006;141:374-382.

2Lucae S, Salayakina D, Barden N, Harvey M, Gagné B, Labbé M, Binder EB, Uhr M, Paez-Pereda M, Sillaber I, Ising M, Brückl T, Lieb R, Holsboer F, Müller-Myhsok B: P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet 2006;15:2438-2445.

3Akhondzadeh 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;8:485-489.

4Machado-Vieira R, Soares JC, Lara DR, Luckenbaugh DA, Busnello JV, Marca G, Cunha A, Souza DO, Zarate CA Jr, Kapczinski F: 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;69:1237-1245.