Can bupropion be added to a combination treatment of fluoxetine and mirtazapine?/nA 28-year-old man

Fråga: Can bupropion be added to a combination treatment of fluoxetine and mirtazapine? A 28-year-old man with depression is being treated with fluoxetine 60 mg and mirtazapine 30 mg daily. He is also a heavy smoker and wishes to try bupropion for smoking cessation.

Sammanfattning: There is a theoretical basis for both pharmacodynamic and pharmacokinetic interactions between the three drugs fluoxetine, mirtazapine and bupropion, as they all have antidepressive properties and are metabolised by the same liver enzymes. Both beneficial and adverse effects have been reported from the combination of two of the drugs. If triple therapy is considered indicated, bupropion should be added with utmost care and awareness of possible adverse effects. A suggestion could be to withdraw mirtazepine during the bupropion treatment, or to use alternative interventions for smoking cessation.

Svar: So far, there are very few studies that systematically have investigated the interactions between more than two drugs.

All three substances fluoxetine, mirtazapine and bupropion have antidepressive properties. Fluoxetine is a serotonin reuptake inhibitor (SRI), mirtazapine increases both noradrenergic and serotonergic neurotransmission, whereas bupropion blocks the neuronal reuptake of norepinephrine and dopamine. All three substances are also extensively metabolised in the liver, mainly by the same enzymes. Fluoxetine is metabolised by the liver enzyme cytochrome (CYP) 2D6, and is also a strong inhibitor of this enzyme. Mirtazapine is metabolised by CYP2D6, but also by CYP1A2 and CYP3A4. Bupropion is metabolised by several different enzymes including CYP2B6, CYP1A2 and CYP3A4 (1). Thus, there is a theoretical basis for both pharmacodynamic and pharmacokinetic interactions.

As could be expected, a literature search did not reveal any specific studies concerning the combination of all three drugs. Nor did we find any such case reports. One case of serotonin syndrom has been reported as resulting from the combination of fluoxetine and mirtazapine. This could be due to the dual serotonergic effects of these two substances (2).

Bupropion has been reported to be safe and possibly effective as add-on therapy in depressed patients with a partial response to SRI-treatment in an open study including 27 patients (3). Bupropion has also been suggested as treatment for SRI-induced sexual dysfunction (4). However, we have found one reported case of panic, caused by the the combination of fluoxetine and bupropion (5).

In combining fluoxetine with mirtazapine, it can expected that the latter drug is mainly metabolised by CYP1A2 and/or CYP3A4, as the CYP2D6 enzyme will be strongly inhibited. Consequently, a possible mirtazapine-bupropion interaction may be more pronounced, than what would be the case if only the latter two drugs are combined.