Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?

Case: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MRp. 2.4) and the clearance of maprotiline (CLM) was 4190 ml.min(-1) (expected CLM = 1220 in extensive metabolisers of CYP2D6). Results: The patient's MRurine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regimen was changed to coadministration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MRp of maprotiline (4.9) and CLM were reduced (1900 ml.min(-1) expected CLM in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease. Conclusion: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient.