Is there any risk of interaction between venlafaxine and mirtazapine?/nThe question concerns a 25-y

Fråga: Is there any risk of interaction between venlafaxine and mirtazapine? The question concerns a 25-year-old man who is being treated with venlafaxin tablets 37.5 mg, 1.5 x2. Addition of mirtazepine is under consideration. Can mirtazepine increase venlafaxin concentration, which is already high, 697 nmol/L for venlafaxine and 266 nmol/L for O-desmethylvenlafaxine? Concomitant drugs: Theralen (alimemazine) 1/4 tablet as needed.

Sammanfattning: We found no reports of interactions between venlafaxine and mirtazepine. Both venlafaxine and mirtazepine are relatively weak inhibitors of CYP450 and risk of clinically relevant drug interactions between them appears to be small, though theoretically possible. A case of possible serotonin syndrome suspected to have been caused by a pharmacodynamic interaction between mirtazepine and fluoxetine was reported.

Svar: We found no reports of metabolic drug interactions between venlafaxine and mirtazepine.

Venlafaxine is extensively metabolised in the liver via cytochrome P450 2D6 to O-desmethylvenlafaxine, which is considered to be equipotent with the parent drug as a nordrenaline and serotonine re-uptake inhibitor (1). Venlafaxine is metabolised to N-desmethylvenlafaxine, CYP3A4 being the major enzyme catalysing this reaction in humans (2). Patients who are deficient of CYP2D6 (poor metabolisers, 7 per cent of the Caucasian population) develop high plasma concentrations of the parent drug and low concentrations of the metabolite (3). Based on the venlafaxine/O-desmethylvenlafaxine ratio of 2.6 in this patient, it is very likely that he is a poor metaboliser of venlafaxine (reference around 0.25) (4). In vitro as well as clinical studies show that venlafaxine is a relatively weak inhibitor of CYP1A2, 2C9, 2D6, and 3A4 (5). Mirtazapine is metabolised by several cytochrome P450 enzymes including 1A2, 2D6 and 3A4. In vitro and in vivo studies show that it is a weak inhibitor of CYP2D6, 1A2 and 3A4 (6). Thus, neither of these two drugs is a potent inhibitor of CYP-mediated drug metabolism. However, as both drugs are substrates of the same enzymes, a metabolic drug interaction can not be excluded.

While mirtazepine and venlafaxine appear to have low risk of metabolic interactions, the possibility of a pharmacodynamic interaction between the two drugs should be considered since both drugs increase the synaptic levels of serotonin in the brain. There is a case of serotonin syndrome described which is suspected to have been caused by an interaction between mirtazapine and another selective serotonin re-uptake inhibitor (SSRI), fluoxetine (7). The case concerned a 75-year-old woman with a chronic depressive illness. She was treated with fluoxetine, 20 mg/day, chlorpromazine, 75 mg/day, and lorazepam 2.5 mg/day. Because of poor effect, fluoxetine was discontinued and instead mirtazepine, 30 mg/day was put on. A few hours after the first mirtazepine dose, the patient developed a severe syndrome with dizziness, headache, nausea, dry mouth, intense anxiety and agitation with suicidal ideas, difficulty in walking, marked resting tremor of the hands and insomnia. The reaction was interpreted as a serotonin syndrome and it resolved after discontinuation of mirtazepine.