Printable Version

Home > Abstracts of Current Literature > Allopurinol for Refractory Schizophrenia

A Clinical Trial of Adjuvant Allopurinol Therapy for Moderately Refractory Schizophrenia

Background: The proposed mechanism for allopurinol, a xanthine oxidase inhibitor, for the treatment of schizophrenia is based on the hypoadenosinergic hypothesis. Adenosine is a neuromodulator of dopaminergic and glutamatergic systems, both of which are altered in schizophrenia. Allopurinol may promote the salvage of purines such as adenosine, increasing the pool of available purines.

Objective: The purpose of this study was to investigate the efficacy of allopurinol as an adjuvant treatment for poorly responsive schizophrenia.

Methods: This was a randomized, double-blind, placebo-controlled, crossover study design. Thirty-five patients were enrolled in the study. Patients were eligible to participate if they were diagnosed with moderately refractory schizophrenia or schizoaffective disorder according to DSM-IV criteria, and if they had been receiving stable treatment with optimal doses of any antipsychotic, except for clozapine, for at least two months prior to the study. Exclusion criteria included the abuse of alcohol or illicit drugs during the previous six months and concurrent medical, neurologic, or other psychiatric disorders. Patients were assigned to receive either allopurinol 300 mg twice daily or placebo for six weeks. After completion of the first treatment phase, patients crossed over to the alternate adjuvant treatment for another six weeks. Schizophrenia and extrapyramidal symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Extrapyramidal Symptom (EPS) rating scale at weeks 0, 3, 6, 9 and 12. Treatment response was defined as a greater than 20% improvement in PANSS scores compared with baseline for the first treatment phase and compared with the last evaluation before crossover for the second phase. Compliance was estimated by counting remaining capsules every 3 weeks (at least 80% had to be taken) and retrospectively by uric acid determination at baseline, 6 and 12 weeks. The P50 auditory evoked potential was assessed for 18 patients at weeks 0, 6 and 12. The study did not report a power, and a modified intent-to-treat analysis was used.

Results: Twenty-two of 35 patients completed the study. One patient who responded to allopurinol dropped out at week 9 (of the placebo phase) due to symptom worsening, but was included in the analysis. Compared to placebo, treatment with allopurinol produced the following point changes in PANSS scores (mean ± SD): Total -12.0 ± 10.0; Positive -5.0 ± 4.5; Negative -2.0 ± 2.6; General -5.0 ± 4.9 (p<0.01 for all). Extrapyramidal symptoms were not altered throughout the study; however, actual results were not reported. Uric acid levels decreased for all patients during allopurinol treatment compared with baseline and placebo levels (baseline 4.5 ± 1.7 mg/dL, placebo 4.9 ± 1.6 mg/dL, allopurinol 2.2 ± 0.9 mg/dL, p<0.001), suggesting compliance with treatment. However, results were not provided for capsule counting. The P50 ratio was 79.8 ± 36.7% at baseline, 61.9 ± 27.0% after allopurinol treatment, and 64.7 ± 48.4% after placebo treatment (p=0.08). The authors concluded that allopurinol was an effective adjunctive treatment strategy for poorly responsive schizophrenia, with advantages in cost, tolerability, availability, and potentially neuroprotective action when compared to existing treatment options.

Strengths: This was a randomized, double-blind study. Appropriate and validated rating scales were used for assessing response to treatment and adverse extrapyramidal symptoms. The crossover design and maintenance of previous medication regimens during the trial may minimize bias related to the presence of concomitant medications.

Weaknesses: Patients were excluded if they had concurrent medical, neurologic, or other psychiatric disorders. This may limit the applicability of the results to the general population of schizophrenic patients. The design did not include a wash-out period, and the possibility of carry-over effect was not accounted for. The study did not report power or confidence intervals. Type II error could have been a factor in this study due to the small sample size and presence of several statistically non-significant results. The study sample was also very heterogeneous, which may affect the study’s validity.

Conclusion: Based on the preliminary results of this study, allopurinol may be an effective adjuvant therapy for certain patients with moderately refractory schizophrenia. Positive symptoms responded better to therapy than negative symptoms. However, additional studies in a larger sample of patients using a parallel study design are desirable before generalization to the public is warranted. A comparative study with clozapine, currently the only well-established treatment for treatment-resistant schizophrenia, would be interesting considering the risks, frequent monitoring, and costs associated with clozapine therapy.

Brunstein MG, Ghisolfi ES, Ramos FLP, Lara DR. A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. J Clin Psychiatry 2005;66(2):213-19.

Julie LeRose, Pharm.D. Candidate