Trond Aamo

Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database.

A compilation of therapeutic drug monitoring data for 15 antidepressant drugs in a naturalistic routine clinical setting is presented. A substantial number of serum concentrations, at different daily doses, are outlined, and the intraindividual and overall serum concentration coefficient of variation for a respective substance is presented. Also, concentration comparisons between women and men, and patients older or younger than 65 years are made. The drugs included are amitriptyline (n = 394), citalopram (n = 5457), clomipramine (n = 400), escitalopram (n = 3066), fluoxetine (n = 793), fluvoxamine (n = 165), mianserin (n = 1063), mirtazapine (n = 1427), moclobemide (n = 200), nortriptyline (n = 206), paroxetine (n = 1677), reboxetine (n = 85), sertraline (n = 2998), trimipramine (n = 158), and venlafaxine (n = 1781). Of the 9 drugs exhibiting linear (first order) kinetics, all but reboxetine gave a significant negative dose-to-dose-normalized correlation with concentrations, that is an increased clearance with higher dose. When dose was correlated to the metabolite:parent substance ratio for drugs exhibiting linear kinetics, citalopram and mianserin gave a positive slope, contrary to a negative slope shown for sertraline and venlafaxine. The intraindividual variations of the serum concentrations were lower than the overall variations, and the intraindividual variation of the metabolite:parent substance ratio was lower than the intraindividual variation of respective parent substance (except clomipramine and mianserin). Women had significantly higher serum concentrations than men (significant for citalopram, escitalopram, mianserin, mirtazapine, and venlafaxine), and patients older than 65 years had higher serum concentrations than the younger ones for all drugs except amitriptyline, moclobemide, and trimipramine. By presenting a comprehensive compilation of therapeutic drug monitoring data for each drug, a reference tool is created, in addition to improved pharmacokinetic knowledge of antidepressant drugs.

Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients

The clinical importance of routine drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. We measured morphine, M6G and M3G serum concentrations in cancer pain patients receiving oral (n = 263, median dose 80 mg/24 hours) or subcutaneous (sc) (n = 35, median dose 110 mg/24 hours) morphine. Regression analyses were performed to investigate if serum concentrations of morphine, M3G and M6G predicted pain intensity (Brief Pain Inventory), health-related quality-of-life variables (EORTC QLQ-C30) and cognitive function (Mini-Mental Score). Serum concentrations were also compared in patients categorized as morphine ’treatment successesfland ‘treatment failures’. We observed that serum concentrations of morphine, M6G or M3G did not predict pain intensity, cognitive function, nausea or tiredness. ‘Treatment failuresflcaused by nausea, tiredness, cognitive failure or constipation did not have statistically significant different morphine, M6G and M3G serum concentrations than patients classified as ’treatment successes’. In conclusion, this study did not observe any concentration–effect relationships of morphine, M3G or M6G with pain intensity, nausea, constipation, tiredness or cognitive failure in blood samples obtained during routine clinical drug monitoring in cancer patients. This result suggests that therapeutic drug monitoring as a routine tool during chronic morphine treatment has limited value for clinical decision making.

Oral dyskinesias and histopathological alterations in substantia nigra after long-term haloperidol treatment of old rats.

The pathophysiologic basis of tardive dyskinesia remains unclear, but several lines of evidence suggest that persistent neuronal changes in the basal ganglia produced by oxidative stress or glutamate toxicity may play a role, especially in the elderly. In the present study we examined whether histopathological alterations in substantia nigra are related to oral dyskinesia in a rodent model of tardive dyskinesia. Haloperidol decanoate (38 mg/kg/4 weeks) was administered to young (8 weeks) and old (38 weeks) rats for a total period of 28 weeks, and the development of vacuous chewing movements (VCM) was observed. Rats with high and low levels of VCM and saline-treated controls were analyzed for histopathological alterations. Reduced nerve cell number and atrophic neurons were prominent features in the substantia nigra of old rats with high levels of VCM. Some alterations were also present in the substantia nigra of the old rats with low levels of VCM and young rats with high VCM levels, but these were significantly less affected than the high VCM rats. These results show that the development of haloperidol-induced oral dyskinesias in old rats is associated with histopathological alterations in the substantia nigra. This suggests that nigral degeneration induced by neuroleptics may contribute to the development of persistent VCM in rats and possibly irreversible tardive dyskinesia in humans.

Inhibition by memantine of the development of persistent oral dyskinesias induced by long‐term haloperidol treatment of rats

1 Tardive dyskinesia (TD) is a serious side‐effect of long‐term treatment with neuroleptics. To investigate if neuroleptic‐induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1‐amino‐3,5‐dimethyladamantane), was studied in a rat model of TD. 2 In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg−1 day−1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg−1 i.p. or saline i.p. In a subsequent long‐term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg−1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long‐term treatment. 3 In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidolinduced increase in the putative TD‐analogue vacuous chewing movements (VCM). 4 In the long‐term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose‐dependently increased VCM and moving during long‐term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co‐treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5 These results suggest that long‐lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.

Macrolide pharmacokinetics and dose scheduling of roxithromycin

The 150- and 300-mg single-dose pharmacokinetics of roxithromycin were investigated in 12 healthy subjects in a crossover study. Serum concentrations were determined by high-performance liquid chromatography (HPLC) and microbiologic assay (MA). Peak serum levels as measured by HPLC were 6.7 +/- 2.6 (150 mg) and 11.0 +/- 2.2 micrograms/ml (300 mg) and did not differ significantly from the values obtained by MA. Mean serum roxithromycin levels 12 hr after the 150-mg dose and 24 hr after the 300-mg dose were 2.50 and 2.55 micrograms/ml, respectively. HPLC analysis of a comparable macrolide, clarithromycin, showed peak serum levels of 1.2 +/- 0.6 and 2.3 +/- 0.6 micrograms/ml after oral dosing with 250 and 500 mg in the same subjects. The 14-OH metabolite reached a level that was 50% and 40%, respectively, of that of the parent compound. Roxithromycin showed a prolonged elimination half-life compared with clarithromycin and its 14-OH metabolite. Mean values of 14.6, 3.5, and 5.5 hr, respectively, indicate the need for less frequent dosing of roxithromycin.

Evaluation of a urine on-site drugs of abuse screening test in patients admitted to a psychiatric emergency unit.

The objective of this study was to characterize the usefulness and reliability of a commonly used urinary on-site drugs of abuse screening test device when used routinely at admittances to a psychiatric emergency unit. Urine samples from 262 emergency psychiatric admittances representing 217 patients were analyzed by a commercially available on-site test for the detection of amphetamines, benzodiazepines, cannabis, cocaine, and opiates in urine. The samples were first screened by nurses at the psychiatric department, thereafter by 2 technicians at the laboratory, and finally, analyzed by liquid chromatography/mass spectrometry. Results of 45.8% of the screening tests were true negative for all 5 drugs/drug groups tested, whereas those of 29.4% were true positive for 1 or several drugs/drug groups and true negative for the others. Thus, in total, 75.2% were correct for all 5 drugs/drug groups. In general, the sensitivities (42.9%-90.0% for the various drug groups) were lower than the specificities (92.7%-100.0%). The accuracies were 86.3% for benzodiazepines, 92.4% for cannabis, 94.7% for opiates, and 97.0% for amphetamines. No cocaine was found in any of the samples. For cannabis, the accuracy was higher among the laboratory technicians than among the nurses. The results from on-site screening testing should not be considered as the final conclusion on the intake of drugs of abuse but must be interpreted with caution.

Adverse drug reactions of antidepressants and antipsychotics: Experience, knowledge and attitudes among Norwegian psychiatrists

Efficient prevention of adverse drug reactions (ADRs) requires knowledge about their severity and pharmacological mechanisms and is dependent on reliable data on their frequencies and possible risk factors. The study was conducted to investigate the prescribers’ experience and understanding of the ADRs of psychotropic drugs, and their attitude towards reporting these. In a questionnaire, physicians treating adult psychiatric patients were asked which ADRs that they regarded bothersome for some of the most widely used antidepressants and antipsychotics. Questions about the relationship between blockade of drug receptors and ADRs, and about the physicians’ personal experience of and attitudes towards reporting of ADRs were also included. In total, 70 of 91 questionnaires (78%) were returned. The mean number of ADRs regarded bothersome ranged from 2.4 to 9.3 for the various drugs/drug classes. Qualified psychiatrists stated a significantly higher number of bothersome ADRs than did the residents. The percentage of physicians associating blockade of a receptor with a specific ADR varied from 76% (histamine receptor blockade and sedation) to 37% (α1-adrenergic blockade and tachycardia). Thirty-nine per cent of the physicians had never reported an ADR to the Norwegian Medicines Agency. The number of ADRs considered bothersome was relatively high. The pattern of these ADRs generally mirrored the typical ADR profiles of the drugs. The knowledge of the underlying mechanisms of ADRs was more or less incomplete. The reporting rate of ADRs to the national regulatory authorities was low.