[Antidepressive drug therapy, suicidal tendency and suicide, 2 cases reported in connection with moclobemide (Aurorix) therapy].
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Aged↗
Biomedical subjects
L F Gram
Publications and source records attributed to L F Gram.
Glucuronidation clearance of 8-hydroxyclomipramine in relation to sparteine and mephenytoin phenotype.
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Clomipramine↗
CYP2D6 genotype determination in the Danish population.
CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for the functional (wild type) gene, D6-wt. However, the D6-wt gene was apparently also present in 11 (12%) of the PM who accordingly were incorrectly genotyped as EM. The specificity of genotyping PM thus was 100% but the sensitivity was only 88%. The most common allele was the D6-wt with an apparent frequency of 0.741 (0.026) in the Danish population and the second most common allele was the D6-B with an apparent frequency of 0.194 (0.024). The median (range) of the sparteine metabolic ratio (MR) in 47 homozygous D6-wt EM was 0.28 (0.11-4.10) and the corresponding value in heterozygous EM was 0.36 (0.11-9.10). The median difference was 0.09 (95% confidence interval: 0.02-0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring.
Adolescent↗
Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms.
The influence of the sparteine and the S-mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomipramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L.hr-1 (range, 68 to 210) in the EMs/EMm subjects, 56 L.hr-1 (range, 37 to 183) in the PMs/EMm subjects, 66 L.hr-1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L.hr-1 in the PMs/PMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C.
Adult↗
Effects of mizolastine, a new antihistamine, on psychomotor performance and memory in elderly subjects.
The effects of a single 10 mg dose of the new H1 antihistamine mizolastine on psychomotor performance and memory in the elderly were assessed in a double-blind, cross-over, placebo-controlled study in 15 elderly female volunteers aged 66-77 years, using clemastine 2 mg as a positive control. Objective (critical flicker fusion, choice reaction time, digit symbol substitution, immediate and delayed free recall) and subjective (linear analogue rating scales) assessments were done on each test day before the dose, then 4 and 8 h post-dose. Plasma samples were also collected. A single oral dose of mizolastine within the range of recommended daily therapeutic dosages (10 mg) failed to induce subjective drowsiness and produced no detrimental effects on psychomotor performance or on short-term and long-term memory in the elderly subjects. In contrast, 2 mg clemastine induced significant impairments (decrease in critical flicker fusion, increase in recognition reaction time) in comparison with placebo and mizolastine, although it did not impair memory. The pharmacokinetic profile of mizolastine in the elderly study subjects was similar to that observed in healthy young volunteers. Therefore, it can be concluded that mizolastine 10 mg could be used safely in elderly out-patients as it preserves functions involved in activities of daily living.
Aged↗
Concurrent use of more than one major psychotropic drug (polypsychopharmacy) in out-patients--a prescription database study.
1. In order to assess the prevalence of concurrent use of more than one major psychotropic drug (polypsychopharmacy) in out-patients, a prescription database study was conducted in the Odense area for a period of 2 years. 2. During the index period 5.12% of the inhabitants purchased major psychotropic drugs. Of these, 14% had a period of polypsychopharmacy recorded. The age-specific prevalence of users increased with age, the prevalence for over 90 years of age was 18%. Sixty-seven per cent of the psychotropic drug users were women. 3. For neuroleptic and antidepressant users, about 20% were subject to polypsychopharmacy, for lithium 61%. The most prevalent combination was neuroleptics-neuroleptics. In none of the 10 most prevalent combinations were the mean daily doses significantly lower on polypsychopharmacy compared with single drug regimens, in two they were higher. 4. Polypsychopharmacy with psychotropic drugs was frequent in out-patients. In polypsychopharmacy daily doses were not lowered in order to limit side effects.
Ambulatory Care↗
Dose-effect relationships for tricyclic antidepressants: the basis for rational clinical testing of new antidepressants.
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Antidepressive Agents, Tricyclic↗
Therapeutic potentials of recently introduced antidepressants. Danish University Antidepressant Group.
The DUAG studies showed that in well-designed and rigorously executed multisite drug trials three representatives (citalopram, paroxetine, and moclobemide) from two classes of recent antidepressant drugs were less effective than the standard reference drug, clomipramine. The most important reasons for the superiority of clomipramine was probably that clomipramine was given in a high and fixed dose of 150 mg per day throughout the entire treatment period and that patient compliance was ensured through drug monitoring. When the DUAG studies are compared with "no difference" studies, the difference between DUAG and others lies not so much in a different efficacy of the test drugs but in the efficacy of the reference drugs, where clomipramine in the DUAG studies was more effective than reference tricyclics in most other studies with flexible dose regimens. A relatively high rate of adverse drug reactions with clomipramine administered in high and fixed doses was probably due to a considerable interindividual variability in the pharmacokinetic properties. (Gram 1990), and the development of side effects may be predicted and prevented when better knowledge of plasma concentration and dose-response relations for classical tricyclic antidepressants allow individual dose adjustments. Such studies are under way with in the DUAG. The results of such studies may reduce the need for new antidepressants which, although less toxic than the classical tricyclics, may prove to be also less potent. The DUAG studies were performed in hospitalized, moderately to severely, endogeneously depressed adult patients and conclusions from the DUAG studies about the superiority of clomipramine over three recent antidepressants cannot readily be generalized to cover less homogeneous groups of outpatients with milder depression.(ABSTRACT TRUNCATED AT 250 WORDS)
Antidepressive Agents↗
Role of genetic polymorphism in psychopharmacology--an update.
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Cytochrome P-450 Enzyme System↗
Drug related hospital admissions. Results from an intervention program.
As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance. A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%. There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments. The intervention may have had an non-specific effect on avoidable DRHs.
Denmark↗
Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine.
Nine extensive metabolizers (EMs) and eight poor metabolizers (PMs) of sparteine took a single oral dose of 100 mg of desipramine HCI before and while taking paroxetine 20 mg per day. Before paroxetine, the median of the total desipramine clearance was 7 times higher in EMs than in PMs (102 and 15 l.h-1 respectively). This confirms that desipramine is extensively metabolized via the sparteine/debrisoquine oxidation polymorphism i.e. by CYP2D6. During paroxetine, the median clearances were 22 l.h-1 and 18 l.h-1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l.h-1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l.h-1 respectively). The increase in this clearance in PMs suggests that paroxetine is an inducer of the alternative, unidentified P450(s) which catalyze(s) the formation of 2-OH-desipramine in this phenotype. Before paroxetine, the median amounts of 2-OH-desipramine glucuronide recovered in urine were 69% and 68% of the total recovery of 2-OH-desipramine in urine in EMs and PMs respectively. During paroxetine, the corresponding values were 77% and 84%.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Outpatient utilization of antidepressants: a prescription database analysis.
A prescription database analysis was conducted to describe the users of antidepressants outside hospitals in the Odense area (207,000 inhabitants) during one year. In total, 1.62% (N = 3360) of the population used antidepressants. Women and users aged over 70 years constituted a disproportionately large part. Seventy-five percent of the patients used tricyclic antidepressants. The estimated daily doses for the tricyclic antidepressants were generally low, the third quartile being less than 100 mg daily. The low doses may be due to antidepressants being used on other indications than depression or that a considerable number of the patients are not given a sufficient dose.
Adult↗
Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.
The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
Citalopram↗
Neuroleptic drug utilization in out-patients--a prescription database study.
1 A prescription database study was conducted to describe the out-patient utilization of neuroleptics in the Odense area (207,000 inhabitants) during a period of 1 year. 2 Neuroleptic drug use is widespread, the period prevalence being 2.45% of the population. 3 The prevalence increases with increasing age. Fifteen percent of the population aged 90 years or more received neuroleptic drugs in spite of the many warnings against side effects in the elderly. 4 Estimated daily doses of neuroleptics were considerably lower than the Defined Daily Dose, probably as a reflection of many neuroleptics being prescribed to non-psychotic patients, in whom lower doses are used. 5 For perphenazine, a comparison of estimated daily doses from this study with doses from patients whose treatment had been adjusted by plasma concentration monitoring showed that generally much lower doses were used by patients included in this study.
Adult↗
Moclobemide treatment causes a substantial rise in the sparteine metabolic ratio. Danish University Antidepressant Group.
A sparteine test was carried out immediately before (n = 37) and during (n = 33) moclobemide treatment (200 mg twice daily) in 37 patients participating in a controlled clinical trial. The sparteine metabolic ratio (MR) did not correlate with the plasma concentration of moclobemide and/or its oxidized metabolite Ro 12-8095, and four sparteine poor metabolisers (PM, MR > 20) had plasma moclobemide concentrations similar to those in extensive metabolisers (EM, MR < 20). The Ro 12-8095/moclobemide ratio tended to correlate negatively with the sparteine MR before and during treatment (rs = -0.32, -0.37). During moclobemide treatment the sparteine MR rose substantially by a factor of 1-103 (median 4.7), and two EM became phenotypically PM. In the PM subjects as well as in one EM patient on cimetidine during both tests, no change in sparteine MR occurred.
Adult↗
Citalopram: interaction studies with levomepromazine, imipramine, and lithium.
The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
Adult↗
The N-demethylation of imipramine correlates with the oxidation of S-mephenytoin (S/R-ratio). A population study.
The metabolism of imipramine was investigated in 106 healthy volunteers, all having a sparteine metabolic ratio (MR) of 0.2-0.5 and hence classified as extensive metabolisers. Each subject was given a single oral dose of 25 mg imipramine hydrochloride and blood for assays of imipramine and metabolites was collected 3 h thereafter. The desipramine/imipramine ratio and the 2-OH-desipramine/2-OH-imipramine ratio in plasma, reflecting the demethylation of imipramine and 2-OH-imipramine, respectively, showed significant negative correlations with the mephenytoin S/R ratio (Spearman rank correlation) (rs): -0.46, P < 0.00002 and -0.41, P < 0.00002). No correlations were found between the 2-hydroxylation of imipramine or desipramine and the mephenytoin S/R. These findings confirm those of an earlier panel study showing that the demethylation of imipramine and 2-OH-imipramine cosegregates in part with the mephenytoin oxidation polymorphism.
Adolescent↗