On the hypersensitivity syndrome induced by the selective serotonin reuptake inhibiting antidepressant Zimeldine : A clinical and experimental study
Sammanfattning: Zimeldine, the first selective neuronal serotonin (5-H1) reuptake inhibitor to be registered as an antidepressant was withdrawn from common use due to an acute flu-like adverse syndrome comprising fever, myalgia and/or arthralgia and signs of disturbed liver function. A few of these patients also developed a peripheral neuropathy, in the most serious form a Guillain-Barré syndrome (GBS). The reaction was tentatively termed a hypersensitivity syndrome (HSS).Patients who had developed a HSS during zimeldine therapy (HSS-patients) were compared to control patients who tolerated the drug.No predictor to the HSS emerged concerning demographic data, psychiatric illness, previous medical history, medications with zimeldine or other drugs, other diseases, professional or nutritional circumstances. Nor was there any sign that HSS-patients who also developed neurological symptoms had a different profile of the HSS than other HSS-patients. Earlier zin1eldine treatment per se was not seen to predispose for development of a HSS or any other kind of adverse experience during subsequent therapy. The spectrum of adverse reactions was in agreement with those reported in previous studies and no new case of the GBS was revealed. The estimated frequency of HSS ranged from 0.63 to 3.4 % in spontaneous reports to the regnlatory authority and 1.4- 13% in a written inquiry. Among closely monitored inpatients 31 %developed a HSS. The mechanism for the HSS does not seem to be related primarily to the 5-HT reuptake inhibition as such. No HLA-associated disposition for the HSS was found. Nor was there any support for a HLA-associated disposition for depressive disorders. The pathogenetic mechanism for the HSS seems to involve an inlmunological response to antigens related to zimeldine.Zimeldine and its main primary metabolite norzimeldine both suppressed clinical signs of experimental allergic neuritis (EAN) in Lewis rats. Imrnunomodulatory effects in vitro of zimeldine, its metabolites norzimeldine and CPP 200 as well as of other monoamine reuptake inhibiting antidepressants were identified in the same EAN model.These observations call for further research on immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of autoimmune diseases. The findings also justify a discussion on the application of immunological methods in the testing of new psychopharmacological drugs.Based on the presented results the tentatively used term for the adverse reactions to zimeldine, the hypersensitivity syndrome, seems justified.
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