Alternate-day dosing to taper antidepressants risks severe withdrawal effects: an in silico analysis

Clinicians often recommend dosing antidepressants every other day when tapering to reduce 'average' daily doses. This is used in place of liquid formulations or other methods for obtaining smaller doses. There is limited evidence to support this approach. This paper explores variation of the inter-dose interval when tapering five widely used antidepressants: citalopram, escitalopram, sertraline, duloxetine, and mirtazapine. We analysed the resultant occupancy of relevant target receptors to establish whether prolonging the interval between doses would likely increase the risk of withdrawal symptoms.

Analysis was conducted in silico using pre-existing pharmacokinetic data including bioavailability, distribution volumes, time to maximal concentration, and elimination half-lives. Modelling was conducted to assess the effect of altered administration frequency. Receptor occupancy was predicted using previous imaging data. We used pre-defined thresholds to evaluate the tolerability of receptor occupancy variation for different dosing strategies.

Prolonging the inter-dose interval led to a pronounced increase in receptor occupancy variation at standard doses of all antidepressants. Variation increased as dosage reduced until the ED₅₀ for each drug, which is often far below doses used in current practice. Therefore, increasing the dose interval at minimum therapeutic doses, or even half of that dose, likely increases the risk of withdrawal symptoms and cannot be recommended as a prudent strategy for tapering.

Dosing every other day is likely to cause withdrawal effects with the antidepressants examined in this study. These recommendations remain theoretical until further clinical research and empirical validation of our proposed antidepressant tapering regimens.