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Interaction of the week: Mirtazapine (Remeron) + Clonidine

Mirtazapine can render clonidine ineffective. This is a pharmacodynamic interaction (opposing mechanisms of action). Mirtazapine may diminish the antihypertensive effect of clonidine, potentially resulting in hypertensive crisis (Abo-Zena et al, 2020; Troncoso AL et al, 2004).

Clonidine is an alpha2 adrenergic receptor agonist. Mirtazapine's principal antidepressant action is blocking alpha2 receptors.

clonidine plus mirtazapine (Remeron) interaction explained

Mirtazapine binds alpha-2A and alpha-2C receptors with higher affinity (smaller Ki) than clonidine.

Here is more information about the receptor binding profile of mirtazapine, which explains its therapeutic effects and side effects.

mirtazapine (Remeron) mechanism of action

The combination of mirtazapine and clonidine is not recommended, but is it absolutely contraindicated?

As shown below, clonidine has sedative mechanisms that are not blocked by mirtazapine. If clonidine were being used off-label for refractory insomnia at low dose, it might still work for that indication even in the presence of mirtazapine.

A patient needing clonidine for opioid withdrawal or ADHD may not benefit much if they are also taking mirtazapine.

Please contact me or comment below if you've identified a reason to prescribe the combo of mirtazapine and clonidine (or other centrally acting alpha-2 agonist) strategically.

clonidine mechanism of action

The endogenous ligand norepinephrine (NE) binds the alpha-2C adrenergic receptor with Ki of ~600. When this occurs centrally (in the CNS), blood pressure is lowered by feedback inhibition. Clonidine does the same with higher binding affinity and without much of the blood pressure-elevating effect brought about by NE at alpha-1 receptors. Mirtazapine binds alpha-2C receptors stronger than either clonidine or norepinephrine. If the patient is not taking clonidine, adding mirtazapine will not appreciably increase blood pressure because normally BP regulation does not rely much on feedback inhibition caused by NE binding to central alpha-2 receptors. But if the patient is relying on clonidine for BP regulation, displacement of clonidine by mirtazapine may result in hypertensive crisis. Note abrupt discontinuation of clonidine under any circumstance is likely to cause rebound hypertension.

clonidine and mirtazapine explained with norepinephrine at alpha-2 receptors

The mirtazapine plus clonidine interaction is also applicable to other medications with clonidine's mechanism of action. These centrally acting alpha-2 agonists include guanfacine (Tenex), lofexidine (Lucemyra), dexmedetomidine (Precedex, Igalmi), tizanidine (Zanaflex), methyldopa, and the horse tranquilizer xylazine.

receptor binding profiles of centrally acting alpha-2 agonists: norepinephrine, guanfacine, lofexidine, xylazine, dexmedetomidine, clonidine, tizanidine

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Jason Cafer MD
Jason Cafer MD
Sep 19, 2023

Along with mirtazapine, clonidine could be used at bedtime for insomnia. Clonidine would still be sedating but would not have BP-lowering effect.

Replying to

i take them both to sleep and it has totally changed my life, i can fall asleep an hour after i take them like clockwork and it makes it super easy to wake up in the morning when they’ve worn off.

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