Sodium valproate increases pupillary responsiveness to a cholinergic agonist in responders with mania

Background: The cholinergic hypothesis of affective disorders predicts that mania is a hypocholinergic state relative to monoaminergic activity. Treatments that increase cholinergic sensitivity are expected to improve manic symptoms. Valproic acid is an effective treatment for mania. Little, however, is known about the cholinergic effects of this agent. Methods: Ten male hypomanic or manic patients were treated with valproic acid (1500–2000 mg) for 2 weeks. Cholinergic sensitivity was assessed before, and after treatment using graded concentrations of pilocarpine eyedrops (0.03–2.0%). Pupil size changes were quantified using an infrared pupillometer and ED50 values were referenced to maximal dilation with 0.5% tropicamide. Results: Valproate treatment decreased Bech mania ratings and ED50 values (p< .0001). Improvements in mania after treatment were closely correlated with decreases in ED50 (r = .76; p< .01). This relationship was indistinguishable from one previously observed after lithium treatment. Conclusions: These results provide support for the cholinergic-adrenergic hypothesis. Moreover, similar pupillary reactions to valproic acid and lithium treatments suggest that these agents may share a common action on muscarinic receptors.