THERAPEUTIC TARGETING OF BRAIN ARACHIDONIC ACID CASCADE IN BIPOLAR DISORDER BY LOW DOSE ASPIRIN AND CELECOXIB.

BACKGROUND

Studies in unanesthetized rats suggest that mood stabilizers approved for treating bipolar disorder downregulate brain arachidonic acid (AA) metabolism. AA plays a role in neurotransmission and neuroinflammation, among other processes. Other drugs that reduce brain AA metabolism may add to mood stabilizer action.

METHODS

We reviewed randomized controlled trials (RCTs) and population studies to examine whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, and acetylsalicylate (aspirin), a COX-1 and COX-2 inhibitor and acetylator, were useful in bipolar disorder patients on mood stabilizers. COX-1 and COX-2 metabolize AA to bioactive eicosanoids.

RESULTS

Celecoxib significantly enhanced mood stabilizer efficacy in two 6-week RCTs involving 86 manic bipolar inpatients, and in one 8-week RCT on 49 patients with treatment-resistant bipolar depression. With regard to aspirin, a Dutch pharmacoepidemiological study involving 5145 subjects taking lithium reported symptom reduction with added chronic low dose 30-80 mg/day aspirin, while a Danish study on 321,350 subjects taking chronic 75-150 mg/day aspirin found fewer manic episodes than in subjects not on aspirin. Finally, a recent 6-week RCT using low-dose aspirin and/or minocycline showed a specific positive effect of aspirin.

CONCLUSIONS

Efficacy of both celecoxib and aspirin as adjuncts to mood stabilizers in the treatment of bipolar disorder is consistent with the AA hypothesis for mood stabilizer action in that disorder.