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Interaction of the week: Atomoxetine (Strattera) + Bupropion (Wellbutrin)

Atomoxetine (Strattera) + Bupropion (Wellbutrin) is a treacherous ADHD combo. I don't prescribe these two together, but it may be appropriate in some situations--see Reddit comment.


Duplication of therapeutic effect: Both medications have the principal therapeutic mechanism of norepinephrine reuptake inhibition.


Bupropion is a strong CYP2D6 inhibitor that increases blood levels of atomoxetine.

Atomoxetine AUC increased 5.1-fold with concomitant bupropion (Todor et al, 2016).

Side effects of elevated atomoxetine may include agitation, insomnia, increased heart rate, and increased blood pressure.

According to the label, atomoxetine may be combined with a strong 2D6 inhibitor, but this is not intended for combination with a medication with the same principal mechanism of action (bupropion). For adults "initiate atomoxetine at a reduced dose of 40 mg/day when combined with strong CYP2D6 inhibitors. The dose should only be increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated."

bupropion wellbutrin mechanism stahl style 797x
Mechanisms of bupropion

stahl style ball of atomoxetine strattera mechanisms of action NET SERT - atomoxetine is a serotonin reuptake inhibitor
Mechanisms of atomoxetine

stahl style interaction between atomoxetine (Strattera) and bupropion (Wellbutrin)
Pharmacodynamic interaction between atomoxetine & bupropion -- they are essentially the same medication

Visualization of interaction between atomoxetine and bupropion
Pharmacokinetic interaction between atomoxetine and bupropion

Cafer's Psychopharmacology bupropion-atomoxetine interaction
Visualize to Memorize representation of the bupropion-atomoxetine interaction

Is atomoxetine an antidepressant?
Medication mascot for atomoxetine from Cafer's Psychopharmacology, to remember generic/trade name pairing

atomoxetine is a CYP2D6 sensitive substrate.
Interaction mnemonic: Atomoxetine is a CYP2D6 sensitive substrate.
bupropion wellbutrin mnemonic
Medication Mascot for bupropion, for memorization of generic/trade name pairing

Bupropion is a CYP2D6 inhibitor and CYP2B6 substrate
Interaction mnemonics for bupropion: CYP2D6 inHibitor (H for high and hurried)

hydroxybupropion is a CYP2D6 substrate
Interaction mnemonic for metabolite hydroxy-bupropion

Mnemonic for CYP450 interactions CYP2D6
From Cafer's Psychopharmacology, CYP2D6 mnemonic framework (H for high & hurried). The D in inDuction is for down & delayed.

paroxetine, fluoxetine, quinidine, duloxetine, and bupropion are examples of CYP2D6 inhibitors
Interaction mnemonics for the major CYP2D6 inHibitors, all of which increase exposure to atomoxetine
Interactions with bupropion
Other CYP2D6 substrates. You probably do not want to combine these with bupropion.

See Auvelity monograph which explains how CYP2D6 inHibition by bupropion can be used for therapeutic effect.

Auvelity interaction
Dextromethorphan is available in a fixed-dose combo pill Auvelity, using 2D6 inHibition by bupropion

FGA interaction between haloperidol (Haldol) and bupropion.
Avoid pimozide and thioridazine concomitantly with bupropion. Adjust dose for haloperidol and perphenazine.

SGA interactions with bupropion - brexpiprazole, iloperidone, aripiprazole
Adjust dose when combining these SGAs with bupropion.

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Great post! Unfortunately, patients come to me on this combo quite often. Someone will start them on wellbutrin for depression / off label ADHD, then they get ADHD dx and are started on atomoxetine target 80mg without d/c wellbutrin. There are obviously the cardiac risks with the inhibition, but they probably get used to the other side effects over time no? (not that this is a good or bad thing)... As far as long term NE inhibition x5 fold- do you feel the body compensates for having such high NE doses (fatigue etc)?

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