Lithium Augmentation of Antidepressant Treatment: Partially due to an Effect on a Cholinergic Mechanism?

To the Editor.—  Recent reports strongly suggest that lithium potentiates the efficacy of tricyclic antidepressants (TCAs).^1-4 Investigators have proposed that this is due to lithium's activation of a presynaptic serotoninergic mechanism.^2,4 This may indeed be a factor. However, other factors may also be contributory.Long-term treatment with TCAs produces dose-dependent supersensitivity of central muscarinic mechanisms.^5,6 Hyperfunction of central muscarinic mechanisms may be involved in the pathophysiology of melancholia.^7-10 Cohen and Baldessarini¹¹ reported that some patients developed tolerance to the antidepressant effects of TCAs. Snider and I⁶ have suggested that the capacity of TCAs to supersensitize muscarinic mechanisms may exacerbate the pathophysiologic defect underlying melancholia.

Materials and Methods.—  We recently found that lithium chloride (160 mg/kg intraperitoneally at 9 AM and 5 PM) blocks the capacity of amitriptyline (10 mg/kg intraperitoneally at 9 AM and 5 PM) to sensitize a muscarinic mechanism in adult