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

Steven C. Dilsaver, MD
Arch Gen Psychiatry. 1988;45(1):96-97. doi:10.1001/archpsyc.1988.01800250112017.
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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


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