Are there any known interactions between mirtazapine and the following drugs: venlafaxine, flupenth

Fråga: Are there any known interactions between mirtazapine and the following drugs: venlafaxine, flupenthixol, digoxin, erythromycin, glibenclamide and insulin? If so, is there a tricyclic antidepressant with less risk of interactions? A 55-year-old male diabetic is being treated for depression with Efexor (venlafaxine) 300 mg/d. Since the effect is not sufficient, addition of Remeron (mirtazapine) is considered. In addition to venlafaxine, the patient is medicating with flupenthixol, digoxin 0.455 mg/d, erythromycin 500 mg/d (long term treatment), glibenclamide and insulin. The plasma concentration of venlafaxine has not been determined.

Sammanfattning: Pharmacodynamic interactions would be expected when venlafaxine is combined with mirtazapine or a tricyclic antidepressant (TCA). This seems to be the desired effect in this case, but the risk of adverse effects (eg serotonin syndrome) by the same mechanism is not known.

Pharmacokinetic interactions with mirtazapine are likely to appear, since it is mainly metabolised by CYP3A4, and the patient is currently taking a potent inhibitor (erythromycin) of this enzyme. The most likely outcome is an increased mirtazapine concentration due to inhibition of its metabolism. Consequently, mirtazapine medication should be cautiously initiated at a low dose, plasma levels determined, and the dose adjusted accordingly.

The risk of pharmacokinetic interactions with TCA:s is probably smaller than with mirtazapine, although there could be a rise in venlafaxine plasma concentration. If co-medication is initiated, monitoring of TCA and venlafaxine plasma levels could be useful. However, we suggest that plasma concentration of venlafaxine is measured before the addition of a second antidepressant is considered.

Svar: One open-design study investigating the response to mirtazapine augmentation in patients with refractory depression was found (1). Five depressed and one dysthymic patient not responding to 4-79 weeks´ treatment with venlafaxine (doses 75-300 mg/d) were given with mirtazapine 15-30 mg/d. After four weeks, 50 per cent of the patients were responding to the medication (Clinical Global Impression-Improvement Scale score of 2 or 3). Sedation was reported in two patients and weight gain in one patient. Except for this study, no information on interactions between mirtazapine and the patient´s current medication was found in Medline, Drugline or standard pharmacological literature.

Mirtazapine has an antagonistic effect on presynaptic alfa-2-adrenergic receptors and postsynaptic 5HT2- and 5HT3-receptors, thereby augmenting the noradrenergic and 5HT1-receptor mediated serotonergic activity (2). Venlafaxine increases synaptic concentrations of noradrenaline and serotonin by inhibiting the reuptake of the two substances (3). A pharmacodynamic interaction would consequently be expected, and actually seems to be the desired effect of the proposed co-medication. Although no substantial evidence of harmful interactions between venlafaxine and mirtazapine was found, there is one case report where co-medication with mirtazapine and a selective serotonin reuptake inhibitor, sertraline, resulted in hypomania (4). Tricyclic antidrepressants (TCA) work in a fashion similar to venlafaxine, albeit not as selective. They inhibit the reuptake of monoamines (5), and pharmacodynamic interactions with venlafaxin would therefore be expected. Theoretically, there could be a risk of serotonin syndrome in co-medication, especially with serotonergic TCA:s such as clomipramine.

Mirtazapine is mainly metabolised by cytochrome P450 isoenzyme CYP3A4 (2). It is a weak inhibitor of this enzyme, as it is of CYP1A2 and CYP2D6 (2, 6). Venlafaxine is metabolised by CYP2D6, and is a very weak inhibitor of this enzyme (7). Erythromycin is a potent inhibitor of CYP3A4 (8) while there is some evidence suggesting that glibenclamide is an inducer of this enzyme (9). Since CYP3A4 is the main route in mirtazapine metabolism, there is a substantial risk of elevated mirtazapin concentrations due to erythromycin medication. It is not known whether flupenthixole, like other neuroleptics, is metabolised by CYP2D6 (10).

All TCA:s are metabolised by CYP2D6 (11, 12). In addition, imipramine and amitriptyline are metabolised by several other enzymes (11, 12). Consequently, there is a vast number of possible pharmacokinetic interactions between these and the current medication. However, no such interactions were found between flupenthixol and imipramine (13) or between erythromycin 1000 mg/d and TCA:s (desipramine, imipramine, doxepine, nortriptyline) (14).