Adenosine hypothesis in schizophrenia and bipolar disorder: A systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators

Objective: Adenosine has been reported to interact with dopamine and glutamate of which are currently central pathophysiology of schizophrenia. Further, there have been emerging reports that patients with bipolar disorder (BD) have pathophysiological changes of the purinergic system. Thus, we performed a systematic review and meta-analysis of adenosine modulators in these disorders. Method: We searched PubMed, EMBASE, the Cochrane Library databases, CINAHL, and PsycINFO up to April 25, 2013. Randomized controlled trials comparing adenosine modulator adjuvant therapy with placebo in patients with schizophrenia and BD were included. Primary outcome measures were Positive and Negative Syndrome Scale (PANSS) and Young Mania Rating Scales (YMRS). The risk ratio, 95% confidence interval, and standardized mean differences (SMD) were used. Results: Nine studies, including six studies in schizophrenia (total n. = 457) and three studies in BD (total n. = 289) were included. Overall, adenosine modulators were superior to placebo in PANSS total scores (SMD. = -. 1.07, p. = 0.01) and positive and general but not negative symptom subscale scores in schizophrenia. Individually, allopurinol failed to show its superiority to placebo in all primary outcome measures in schizophrenia. In BD, data from pooled adenosine modulators indicated significant reduction of YMRS scores in comparison to placebo (SMD. = -. 0.39, p. = 0.004). Conclusions: Our results suggest that adenosine modulator adjuvant therapy is more beneficial in overall psychopathology (especially positive symptoms) in schizophrenia and in treating mania episodes of BD in comparison to placebo. The limited sample size of available studies suggests that more research should be done to evaluate both efficacy and tolerability of these medications.