Under-reporting of serious adverse drug reactions in Sweden.

INTRODUCTION: Adverse drug reactions (ADR) constitute a major problem, both from a medical point of view and as an economical burden. Spontaneous reporting of ADRs is one of the methods for post marketing surveillance of drug safety. Under-reporting can also provide an important obstacle to rapid and relevant signal detection. AIM: To investigate the rate of under-reporting serious ADRs of selected ICD 10 diagnoses. METHOD: In order to investigate the under-reporting rate we investigated at five hospitals within the county of Norrbotten in Sweden the total number of diagnosed cases during a period of 5 years (1996-2000) with the following diagnoses: cerebral haemorrhage (I 61.0-I 61.9), pulmonary embolism (I 26.0 and I 26.9), embolism or thrombosis (I 74.0-I 74.9), phlebititis, thrombophlebitits or venous thrombosis (I 80.0-I 80.3, I 80.8 and I 80.9) and portal vein thrombosis and other thrombosis or emboli (I 82.0-I 82.3, I 82.8 and I 82.9). The identity of these patients was obtained through a database search. The patients' case records were then scrutinized by a specially trained nurse and the drugs used at the time of the event were noted. An assessment of the possibility of an ADR was performed using standard WHO causality criteria. Later, database search in the Swedish ADR registry was performed in order to investigate whether these suspected ADRs had been reported to the national authority in Sweden or not. RESULTS: In total 1349 case records were found and scrutinized. Of these, 107 patients had received drugs that could have been a probable or possible cause to the diagnoses. Of these 92 cases had not been reported and only 15 patients were found in the database, giving an overall under-reporting rate of all ADRs of 86%. The most commonly occurring diagnoses were cerebral haemorrhage followed by venous thrombosis, 545 and 468 respectively. Among those cases that should have been reported according to the existing rules for spontaneous reporting of suspected ADRs the most frequently occurring diagnosis was cerebral haemorrhage (I 61.0) in connection to treatment with anticoagulants. CONCLUSION: The rate of spontaneous ADR reporting is very low, also for serious and fatal reactions.

Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid.

OBJECTIVE: The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers. METHODS: In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h. RESULTS: Carbamazepine decreased the mean total area under the serum concentration-time curve of simvastatin and simvastatin acid by 75% ( P<0.001) and 82% ( P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% ( P<0.01), and half-life of simvastatin acid was shortened from 5.9+/-0.3 h to 3.7+/-0.5 h ( P<0.01) by carbamazepine. CONCLUSION: Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.

Utilization pattern of metamizole in northern Sweden and risk estimates of agranulocytosis.

OBJECTIVE: This study was carried out in order to investigate the utilization pattern of metamizole to better estimate the quantitative risk of agranulocytosis since a cluster of such cases have been observed in Sweden. METHODS: Cases of agranulocytosis submitted to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) between 1996 and 1999 were identified. Based on the utilization pattern of metamizole in inpatients at three hospitals and in outpatients in two counties in northern Sweden risk estimates of agranulocytosis during metamizole treatment were estimated. The utilization of metamizole was investigated by scanning 3567 case records at 10 hospital departments as well as stored prescriptions at six pharmacies during a 3-month study period. RESULTS: Ten cases of agranulocytosis during treatment with metamizole have been reported to SADRAC over the period 1996 to 1999. During the 3-month study period metamizole was prescribed to 666 (19%) inpatients. Of these, approximately 96% received the drug for less than 1 week, 7.2% had used the drug previously. At the participating pharmacies 112 metamizole prescriptions for outpatients were found. The drug was prescribed in 34% for less than 1 week, in 28% for 7-15 days, and in 38% for more than 15 days. The mean prescribed daily dose was 2.7 g. Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients. CONCLUSION: This study indicates that in most inpatients the use of metamizole in northern Sweden was within the approved indications for the drug. However, a considerable number of outpatients received the drug for a longer time than recommended and this may carry an increased risk for developing agranulocytosis.

Spontaneous reporting of adverse drug reactions by nurses.

BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) remains one of the most effective methods to detect new and serious drug reactions. However, it is well known that there is a high degree of under-reporting. OBJECTIVE: This study was carried out as an attempt to improve and increase the reporting of ADRs by investigating the utility of nurses reporting in addition to physicians, as usual. METHODS: During a 12-month study period, nurses working at two departments of geriatric medicine in northern Sweden received special instruction regarding drugs and ADRs, ADR reporting and special aspects of ADRs in elderly people. The reports from the nurses were scrutinized concerning the seriousness of the reaction, reported drugs and type of reaction (type A or B). All nurses working at the two departments (117) were eligible to report but in practice only those attending the teaching sessions did so. A comparison with historical reporting and with reporting from other geriatric departments in Sweden was also carried out. At the end of the study all participating nurses received a questionnaire aimed at investigating their attitudes towards ADR reporting. RESULTS: After the 12-month study period 18 ADR reports involving 22 reactions had been received. Seven of these were assessed as serious reactions. All of the reactions were of type A. In comparison, during the corresponding time period from the study clinics during the preceding year, only two reports were registered. During the study period only 15 reports were registered from the other 50 geriatric departments in Sweden. CONCLUSION: Even though the total number of ADR reports was small, our data indicate a substantial increase in the reporting rate. This indicates that instructed and interested nurses could play an important role in detecting and reporting suspected ADRs.

Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes.

OBJECTIVE: Limited data suggest that CYP1A2 and CYP2D6 are involved in the metabolism of olanzapine. The purpose of this study was to further elucidate the role of these enzymes in the disposition of olanzapine in vivo. METHODS: Seventeen healthy non-smoking male volunteers were included in the study. Five subjects were CYP2D6 poor metabolisers (PMs), and 12 were CYP2D6 extensive metabolisers (EMs). All subjects received a single oral dose of 7.5 mg olanzapine, and serum concentrations were measured for 96 h using gas chromatography. A cross-over study was undertaken in the 12 CYP2D6 EMs who at least 2 weeks before or after the olanzapine dose received a single oral dose of 200 mg caffeine. The concentrations of caffeine and paraxanthine were measured in saliva 10 h after caffeine intake, and the paraxanthine/caffeine ratio was calculated as a measure of CYPIA2 activity. RESULTS: A threefold inter-individual variability in oral clearance (CLoral) and maximum serum concentration (Cmax) of olanzapine was observed and a 2.3-fold inter-individual variability in CYPIA2 activity. There was no significant correlation between CYP1A2 activity and oral clearance of olanzapine (r=-0.19, P=0.56). Moreover, there were no significant differences in any of the olanzapine pharmacokinetic parameters between the CYP2D6 PMs and EMs (CLoral=0.246 l h(-1) kg(-1) and 0.203 l h(-1) kg(-1), respectively, P=0.30). CONCLUSION: Neither CYP1A2 nor CYP2D6 seem to have a dominating role in olanzapine biotransformation after intake of a single dose.

Incorrect use and limited weight reduction of orlistat (Xenical) in clinical practice. A cohort study.

OBJECTIVE: To study the prescribing of the antiobesity drug orlistat in relation to the approved indication and its weight-reducing effect in clinical practice during the first 3 months of treatment. METHODS: Anonymous postal questionnaire survey to prescribers of orlistat concerning a random sample of 1000 of 20,000 prescriptions. PARTICIPANTS: Useful information was obtained for 789 patients. SETTING: Primary and secondary care in Sweden. MAIN OUTCOME MEASURES: Beginning and continued treatment according to the approved indication. Dropout from treatment. Weight loss during treatment. RESULTS: Four percent of the patients were prescribed orlistat despite having a body mass index (BMI) less than 28 kg/m2. Only 24% of the patients had a diet period with a weight loss of 2.5 kg or greater before the start of therapy. Half of the patients with a weight loss of less than 5% after 3 months continued the treatment. Ten percent gained weight or had no weight loss at all while 43% lost less than 5% in weight. At least one-quarter of the patients stopped the treatment within the observation period. CONCLUSION: Orlistat was not prescribed according to the approved indication in the majority of cases. The dropout rate was high and most patients had minor gain from the treatment.

Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers.

AIMS: The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers. METHODS: Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18-49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study. RESULTS: The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was significantly lower than in males (0.067 vs 0.080; P = 0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03-0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a significantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P < 0.001) (mean difference in ln mephenytoin S/R ratio 0.082, 95% CI 0.60-1.04). Moreover, females using combined OCs had a significantly higher median ratio than females using OCs with progestins only (median 0.258 vs 0.135; P = 0.008) (mean difference in ln mephenytoin S/R ratio 0.82, 95% CI 0.21-1.34). CONCLUSIONS: Given certain assumptions, the study indicates that females in the fertile age have a slightly higher CYP2D6 activity compared with males. There was no evidence of a gender difference in CYP2C19 activity. The use of combined OCs reduces the activity of CYP2C19, an effect that seems to be related to the ethinyloestradiol component.

The major fluvoxamine metabolite in urine is formed by CYP2D6.

OBJECTIVE: Previous studies have shown that fluvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the different metabolic pathways of fluvoxamine biotransformation. The present study was designed to investigate this issue. METHODS: The major fluvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50 mg fluvoxamine, and the formation clearance for the metabolite (CLm) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the non-smoking EMs, 200 mg caffeine was given at another occasion in order to calculate oral caffeine clearance as a measure of CYP1A2 activity. In addition, CLm was calculated in ten other subjects given increasing doses of fluvoxamine for 4 weeks. RESULTS: Oral clearance of fluvoxamine was significantly higher in smokers, and significantly lower in CYP2D6 PMs than in non-smoking EMs. CLm was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not influence CLm. There was no significant correlation between oral caffeine clearance and CLm. CLm decreased with increasing fluvoxamine dosage, but the decrease in oral clearance was even higher. CONCLUSION: These results indicate that CYP2D6 catalyzes the major metabolic pathway of fluvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasing fluvoxamine dosage.

HMG-CoA reductase inhibitors and myotoxicity.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors specifically inhibit HMG-CoA reductase in the liver, thereby inhibiting the biosynthesis of cholesterol. These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease. The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. Occasionally, arthralgia, alone or in association with myalgia, has been reported. In this article we review scientific data provided via Medline, adverse drug reaction case reports from the Swedish Drug Information System (SWEDIS) and the World Health Organization's International Drug Information System (INTDIS) database, focusing on HMG-CoA reductase inhibitor-related musculoskeletal system events. Cytochrome P450 (CYP) 3A4 is the main isoenzyme involved in the metabolic transformation of HMG-CoA reductase inhibitors. Individuals with both low hepatic and low gastrointestinal tract levels of CYP3A4 expression may be at in increased risk of myotoxicity due to potentially higher HMG-CoA reductase inhibitor plasma concentrations. The reported incidence of myotoxic reactions in patients treated with this drug class varies from 1 to 7% and varies between different agents. The risk of these serious adverse reactions is dose-dependent and may increase when HMG-CoA reductase inhibitors are prescribed concomitantly with drugs that inhibit their metabolism, such as itraconazole, cyclosporin, erythromycin and nefazodone. Electrolyte disturbances, infections, major trauma, hypoxia as well as drugs of abuse may increase the risk of myotoxicity. It is important that the potentially serious adverse reactions are recognised and correctly diagnosed so that the HMG-CoA reductase inhibitor may at once be withdrawn to prevent further muscular damage.

Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis.

OBJECTIVE: To study the effects of severe renal failure and haemodialysis on the pharmacokinetics of citalopram. METHODS: Four patients with renal failure undergoing haemodialysis and eight healthy controls were given a single dose of citalopram. The concentrations of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were measured in serum and urine. On a different day, the four patients undergoing haemodialysis were given another single dose of citalopram, and the drug concentrations were measured in serum from the artery leading to the dialyser and in the dialysate. In addition, one anuric patient treated with citalopram on a regular basis was included in the study. RESULTS: There were no significant differences between the two groups in any of the pharmacokinetic parameters with the exception of the renal clearance of citalopram, which was significantly lower in the renal failure group than in the control group (1.70 ml/min versus 66.2 ml/min, P<0.001). Oral clearance of citalopram was almost identical in the two groups (452 ml/min versus 456 ml/min). The process of haemodialysis cleared about 1% of the dose as citalopram and 1% as desmethylcitalopram only. CONCLUSION: Severe renal failure does not affect the pharmacokinetics of citalopram and modification of the usual citalopram dose does thus not seem to be necessary. The contribution of haemodialysis to the total elimination of citalopram is negligible.

Attitudes to reporting adverse drug reactions in northern Sweden.

OBJECTIVES: This study was designed to investigate attitudes of general practitioners (GPs) and hospital physicians in Sweden towards spontaneous reporting of adverse drug reactions (ADRs). METHOD: Two areas in the northern region of Sweden were selected for the study. A knowledge and attitude questionnaire followed by a reminder letter 2 weeks later was addressed to all GPs and hospital physicians in the study areas. RESULT: The total response rate from the study areas was 748 of the 1274 questionnaires sent out (58.7%). Of those who responded, 236 were GPs, 433 were hospital physicians and 79 had other positions. Of the responders, 252 stated that they had never reported any ADR and 488 that they had reported at least once in their career. Issues that came out as important in the decision to report or not to report were whether the reaction was considered well-known or not, the severity of the reaction, hesitance to report only on suspicion, lack of knowledge of existing rules, giving priority to other matters and lack of time to report ADRs. Only minor differences in these regards were observed between male and female physicians. CONCLUSION: Our investigation shows that the physicians in northern Sweden have a fairly good knowledge about the existing rules for reporting ADRs in Sweden. However, the attitudes leave room for considerable under-reporting due to matters related mainly to the medical impact of the reaction and of reporting it, but also to the scientific "paradox" of reporting only on suspicion and of course due to lack of time in the health care setting.

Effect of caffeine on clozapine pharmacokinetics in healthy volunteers.

AIMS: To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. METHODS: This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day-1, range: 400-1000 mg day-1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. RESULTS: A 19% increase in mean clozapine AUC(0,infinity) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0, 12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (-18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (-23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0, 12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). CONCLUSIONS: These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.

Absence of interaction between erythromycin and a single dose of clozapine.

OBJECTIVE: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. METHODS: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0-12 h. RESULTS: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h x l(-1) in the control phase and 1180 (659) nmol h x l(-1) in the erythromycin phase), terminal halflives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol x l(-1) and 77 (40) nmol x l(-1), respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l x h(-1) and 46 (37) l x h(-1), respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l x h(-1) and 7.8 (9.4) l x h(-1), respectively) or to desmethyl-clozapine (1.5 (1.3) l x h(-1) and 1.8 (1.7) l x h(-1), respectively) or in renal clearances of clozapine (0.8 (0.5) l x h(-1) and 1.0 (0.7) l x h(-1), respectively) between the two phases. CONCLUSION: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.

Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance.

OBJECTIVE: Evidence exists to suggest that fluvoxamine is metabolized by CYP1A2. The present study was undertaken in order to further elucidate the role of CYPIA2 in fluvoxamine disposition. METHODS: Twelve healthy non-smoking male volunteers participated in this cross-over study. Six subjects received first fluvoxamine 50 mg as a single oral dose and, some weeks later, caffeine 200 mg as a single oral dose. The other six subjects received the drugs in reverse order. Serum concentrations of fluvoxamine, caffeine and paraxanthine were measured and standard pharmacokinetic parameters were calculated. RESULTS: There were no significant correlations between caffeine clearance and fluvoxamine oral clearance (rs = -0.30; P = 0.43) or between the paraxanthine/caffeine ratio in serum 6 h after caffeine intake and fluvoxamine oral clearance (rs = -0.18; P = 0.58). CONCLUSION: CYP1A2 does not appear to be of major importance in the metabolism of fluvoxamine.

Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications.

BACKGROUND: Recent case reports suggest the association of the emergence of diabetes mellitus with clozapine treatment, although conventional neuroleptics have also been implicated. This study was conducted to determine if there is an increased risk of diabetes mellitus and/or impaired glucose tolerance (IGT) during clozapine treatment compared with treatment with conventional depot neuroleptics. METHOD: In a district hospital in northern Sweden, blood glucose tests and, if necessary an oral glucose tolerance test were used to assess the prevalence of diabetes mellitus or IGT in 63 patients treated with clozapine compared with 67 patients treated with conventional depot neuroleptics (haloperidol, zuclopenthixol, fluphenazine, perphenazine, or flupenthixol). Diabetes mellitus and impaired glucose tolerance were classified according to World Health Organization criteria. RESULTS: There were 3 dropouts in the clozapine group and 4 in the control group. Of subjects treated with clozapine, 12% (7/60) had type 2 diabetes mellitus, and 10% (6/60) had IGT. Of subjects treated with depot injections of neuroleptics, 6% (4/63) had type 2 diabetes mellitus and 3% (2/63) had IGT. None in either group had type 1 diabetes mellitus. Subjects in the clozapine group were significantly (p < .001) younger than subjects in the control group, whereas the 2 groups did not differ with respect to body weight, body mass index, or prevalence of diabetes mellitus in first-degree relatives. CONCLUSION: Subjects treated with clozapine were more often classified as having type 2 diabetes mellitus or IGT compared with subjects in the control group. This difference did not, however, achieve statistical significance (p=.06).

Non-linear fluvoxamine disposition.

AIMS: To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers. METHODS: Ten healthy, non-smoking men were given maintenance treatment with fluvoxamine for 4 weeks. Eight subjects were CYP2D6 extensive metabolisers (EMs) and two were CYP2D6 poor metabolisers (PMs). As a measure of the CYP1A2 phenotype, the paraxanthine/caffeine ratio in saliva after intake of caffeine was studied. The fluvoxamine doses given were 25 mg day(-1) the first week, 50 mg day(-1) the second week, 100 mg day(-1) the third week and 200 mg day(-1) the fourth week, divided in two daily doses. On the seventh day every week, serum concentrations of fluvoxamine were followed for a dose interval of 12 h. After discontinuation of treatment, fluvoxamine concentrations were followed for 1 week. RESULTS: For each of the three two-fold increases in given dose, the mean AUC increased 3.25-fold, 3.17-fold and 3.14-fold, respectively (P < 0.0001), indicating a decrease in oral clearance with increasing dose. The elimination half-life based upon the serum concentrations 12-48 h after discontinuation of fluvoxamine was 32.1 +/- 11.0 h whereas the half-life based upon the concentrations 3-7 days after discontinuation was significantly shorter, 15.8 +/- 4.2h (means +/- s.d.; P < 0.001). There were no significant correlations between the CYP1A2 phenotype and fluvoxamine AUCs at different doses (r = -0.56; P = 0.095 for the correlation between the paraxanthine/caffeine ratio in saliva and fluvoxamine AUC at a dose of 50 mg day[-1]). The two CYP2D6 PMs had AUC values in the same range as the EMs. CONCLUSIONS: The present study conclusively demonstrates that fluvoxamine exhibits non-linear kinetics within the therapeutic dose interval. The reason for non-linearity is not Michaelis-Menten saturation kinetics of a single metabolic pathway, but rather a complex involvement of multiple parallel pathways.

Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors.

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.