Can clozapine be combined with methotrexate (MTX) at antirheumatic doses (7.5 mg/week) without incr

Fråga: Can clozapine be combined with methotrexate (MTX) at antirheumatic doses (7.5 mg/week) without increasing the risk of bone marrow toxicity?

The question concerns a patient with Parkinson´s disease and a rheumatic disorder, who is treated with MTX. The patient´s physician is considering treating Parkinson-associated psychotic symptoms with clozapine, but is concerned about a possible interaction with MTX.

Sammanfattning: Theoretically, synergistic adverse effects of methotrexate and clozapine on the bone marrow seem unlikely. The published literature, however, is not extensive enough to provide positive support for this assertion. Pragmatically, the co-medication could be attempted with close supervision of the neutrophil count, if the indication for co-treatment is very strong. Otherwise the combination should probably be avoided, pending further evidence.

Svar: Clozapine treatment-associated neutropenia or agranolucytosis has an incidence of 0.05-2% of treatments. The variation in this figure is due to differing definitions of neutropenia/agranolycytosis, and differing ethnic susceptibility, where azkenazi jewish and finnish seem to be at higher risk. Some data indicate that the risk might be correlated to HLA-type, but these data are not consistent. No clear correlation between dose (or concentration) and risk has been seen. For this reason the adverse effect of clozapine on the bone marrow are generally thought to be due to immunological or possibly metabolical idiosyncrasies (1).

Through the Medline we have been able to detect five single case reports of clozapine treatment during intercurrent anticancer chemotherapy. Four of these have been available in full text or abstract form. Three of these do not indicate any synergistic effects of cytostatics and clozapine on the bone marrow (2,3,4), whereas one author implies that persistent neutropenia after chemotherapy might have been due to clozapine. No formal proof for this, however, is offered (5).

The literature does not offer empirical evidence nor theoretical implications of any likelihood of pharmacokinetic interactions between clozapine and MTX. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993;329:162-7. Hundertmark J, Campbell P. Reintroduction of clozapine after diagnosis of lymphoma. Br J Psychiatry 2001;178:576. Bareggi C, Palazzi M, Locati LD, Cerrotta A, Licitral L. Clozapine and full-dose concomitant chemoradiation therapy schizphrenic patient with nasopharyngeal cancer. Tumori 2002;88(1):59-60. Wesson ML, Finnegan DM, Carlk PI. Continuing clozapine despite neutropenia. Br J Psychiatry 1996;168(2):217-20. Rosenstock J. Clozapine therapy during cancer treatment. Am J Psychiatry 2004;161(1):175.