The question concerns a 48-year-old man, suffering from depressive symptoms for several years. He h

Fråga: The question concerns a 48-year-old man, suffering from depressive symptoms for several years. He has been treating himself with a number of drugs. Three days ago, January 24th, he was admitted to the hospital with signs of confusion, disorientation and visual hallucinations. For the last three months, he has been taking Tolvon (mianserin) 30 mg x3 daily and Fevarin (fluvoxamine) 150 mg x1 daily. During the week before admission, he has also been taking Fluanxol (flupenthixol) 3 mg daily, later switching to Mallorol (thioridazine) 200 mg daily. He was also treated with Imovane (zopiklon) 7.5 mg at night, Theralen (alimemazine) 40 mg now and then and Seloken (metoprolol) 100 mg per day. All drugs, except for the Seloken, were withdrawn at admission and the patient´s symptoms disappeared within 24 hours. Could his symptoms have been caused by an interaction between these drugs?

Sammanfattning: It can be assumed that the patient in this case was suffering from toxic mianserin levels, possibly enhanced by the adverse effects of the other drugs he was taking. The high levels of mianserin may have been caused by a high intake of the drug and/or a metabolic interaction: mianserin, thioridazine, metoprolol and probably flupenthixol are metabolized by and therefore competing for the same isoenzyme, CYP2D6. In conclusion, it seems likely that the patient´s symptoms of confusion and hallucinations were a consequence of the adverse effects of a multiple drug therapy with antidepressants, neuroleptics and a beta-blocker.

Svar: Mianserin is a tetracyclic piperazinozepine compound which is administered as a racemic mixture (1). The drug has an elimination half-life of around 30 h (2,3). Mianserin is extensively metabolised in the liver by hydroxylation to 8-hydroxymianserin, by demethylation to desmethylmianserin and by N-oxidation to mianserin N-oxide (4). Both desmethylmianserin (the major metabolite) and 8-hydroxymianserin have pharmacological properties indicating antidepressant activity (1). Recently, it was found that the elimination of both mianserin and desmethylmianserin depends on the polymorphic CYP2D6 enzyme activity (5). According to FASS (3), the mianserin dosage which is usually effective lies between 30 and 90 mg per day. However, the plasma levels of both mianserin and desmethylmianserin vary widely between patients treated with the same dose (6). There is no established therapeutic window for the plasma concentration of mianserin. However, a concentration range of 100-300 nmol/l is used as a guideline (7). Adverse effects which can be seen in cases of overdose are sleepiness, vomiting, hypotension, hypertension, sinustachycardia, bradycardia, dizziness and ataxia (8).

Concerning hallucination as a side-effect of mianserin, only one case report could be found (9). The Swedish Adverse Drug Reactions Advisory Committee has received three reports since 1983 concerning hallucinations caused by mianserin (10). In two of these cases, the causal relationship was considered to be probable, in one case possible.

Fluvoxamine is eliminated mainly in the liver by oxidative demethylation into a number of (inactive) metabolites. Fluvoxamine is a potent inhibitor of the N-demethylation of tricyclic antidepressants such as amitriptyline, clomipramine and imipramine. It is also a strong inhibitor of CYP1A2 (involved in the metabolism of imipramine and theophylline among others) (11). The drug has a plasma half-life of 17-22 hours (12). There is no recommended therapeutic window for the plasma concentration of fluvoxamine. However, a range of 230-920 nmol/l has been used in practice (13). Commonly observed adverse effects are nausea, somnolence, insomnia, agitation, nervousness, tremor, diarrohea, and asthenia. Hallucinations and delirium have been reported as rare side-effects of fluvoxamine treatment (12,14).

A number of neuroleptics, such as thioridazine, zuclopenthixol and probably also flupenthixol, are at least partly metabolised by the CYP2D6 enzyme (15). Thioridazine is considered a strong inhibitor of CYP2D6 (16).

Metoprolol is extensively metabolised by the liver via three oxidative pathways: O-demethylation, aliphatic hydroxylation and oxidative deamination. The former two pathways are also catalysed by CYP2D6 and therefore impaired in poor metabolisers of debrisoquine (17).

Blood samples were taken from this patient for measurement of mianserin and fluvoxamine concentrations three days after admission. The concentration of mianserin was 364 nmol/l. Assuming roughly a half-life of 30 hours, this would imply that on the day of admission the patient had a plasma level of around 1400 nmol/l. The concentration of fluvoxamine was 75 nmol/l. Assuming a half-life of 20 hours, this would mean a plasma concentration of around 1000 nmol/l on the day of admission.

It can be assumed that the patient was intoxicated by mianserin on the day of admission. This could have been caused by a high intake of the drug itself. Secondly, a metabolic interaction between mianserin and the other drugs the patient was taking seems very plausible; mianserin, thioridazine, metoprolol and most probably also flupenthixol are all (partly) metabolised by CYP2D6. Fluvoxamine and thioridazine could be called inhibitors of this enzyme system. This competition for and inhibition of CYP2D6 (or other P450s) could have inhibited the metabolism of mianserin, leading to toxic plasma levels. It should be added that pharmacodynamic interactions between these drugs could also have been of importance in producing the patient´s symptoms. 1 Hand TH, Marek GJ, Seiden LS: Comparison of the effects of mianserin and its enantiomers and metabolites on a behavioral screen for antidepressant activity. Psychopharmacoly 1991: 105: 453-458 2 Timmer CJ, Pourbaix S, Desager JP, Sclavons M, Harvengt C: Absolute bioavailability of mianserin tablets and solution in healthy humans. Eur J Drug Metab Pharmacokin1985; 10: 315-323 3 FASS 1994; 943-944 4 Pinder RM, van Delft AML: The potential therapeutic role of the enantiomers and metabolites of mianserin. Br J Clin Pharmacol 1983; 15: 269S-276S 5 Dahl ML, Tybring G, Elwin CE, Alm C, Andreasson K, Gyllenplam M, Bertilsson L: Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism. Manuscript for Clin Pharmacol Ther 1994 6 Otani K, Sasa H, Kaneko S, Kondo T, Fukushima Y: Steady-state plasma concentrations of mianserin and its major active metabolite, desmethylmianserin. Ther Drug Monit 1993; 15: 113-117 7 Personal communication Carl-Eric Elwin, Klin farm lab, Danderyds sjukhus 8 The Dutch drug catalogue: farmacotherapeutisch kompas, Ziekenfondsraad, 1993; page 53 9 Koponen H, Honkonen S, Partanen J, Riekkinen PJ: Epileptic attack, delirium, and periodic complexes in the EEG during mianserin treatment. J Neurol Neurosurg Psychiatry 1991; 54: 379

10 Swedis
11 Brosen K: The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Investig 1993; 71:
12 FASS 1994; page 387
13 Personal communication Klin farm lab, St Lars sjukhus, Lund
14 Dollery, Therapeutic drugs. 1992; page 100

15 Dahl ML, Bertilsson L: Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 1993; 3: 61-70 16 Personal communication Leif Bertilsson 17 Dollery, Therapeutic drugs. 1992; page 157