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Objectives: In industry-generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions. Methods: Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up-titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models. Results: For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41-1.22). There was no between-group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine-related, of benign rash occurred. Conclusions: No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome.

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months.METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16).RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed.DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

BACKGROUND: The objectives of the study were to compare efficacy and tolerability of venlafaxine ER 75-150 mg/day with that of citalopram 10-20 mg/day in elderly patients with major depression according to DSM-IV criteria. METHODS: A randomised, double-blind, parallel group 6-month study. Efficacy was assessed by MADRS, CGI Global Improvement, CGI Severity of Illness and GDS-20 scores and safety by physical examinations, vital signs, adverse events and UKU side effect rating. Plasma levels of venlafaxine, its major metabolite O-desmethylvenlafaxine and citalopram were followed. RESULTS: One hundred and fifty-one male and female patients (64-89 years) were enrolled and 118 patients completed the study. Comparable improvements in MADRS, CGI Severity of Illness, CGI Global Improvement and GDS-20 were observed during venlafaxine and citalopram treatment. The MADRS remission rate was 19% for venlafaxine and 23% for citalopram. Side effects were common during both treatments but differed in tremor being more common during citalopram and nausea/vomiting during venlafaxine treatment. There were no clinically significant changes in blood pressure or body weight. CONCLUSION: The observed benefits of venlafaxine treatment in elderly patients with major depression were similar to those observed in younger adults as were reported adverse events and side effects. Treatment with venlafaxine ER was well tolerated and induced beneficial effects of similar magnitude as those of citalopram.

Background: Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA. Objective: To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine. Methods: The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks’ duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales. Results: The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine ( p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine. Conclusion: Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine.

Aims Several studies have found that compliance with lipid-lowering drug (LLD) treatment is low. However, the results of these studies were based on crude measures of compliance. The aim of this study was to describe compliance with statin treatment by analysing prescription patterns on an individual level in a population-based prescription database over a 6 year period. Methods For incident statin users, all prescriptions for statins and drugs indicating cardiovascular disease or diabetes were retrieved from the OPED prescription database covering a population of about 470 000 inhabitants. Treatment was considered discontinued if the interval between two prescriptions exceeded number of tablets prescribed, plus 30 days. Compliance was assessed in terms of persistence and continuity. Persistence was defined as the period from the first prescription date to the date of discontinuation. Continuity was defined as the number of days with treatment (=number of tablets) divided by the total number of days in the period of persistence. Results 11% of the study cohort only received a single statin prescription. Survival analyses revealed a median persistence of 41 months. Less than 15% of the patients had more than 20% days without therapy within the period of persistence. Patients under 45 years without drug indicators of cardiovascular disease or diabetes presented the lowest compliance. Conclusions The study showed good compliance with statin treatment in terms of persistence and continuity. A high percentage of the youngest patients, however, seemed to discontinue treatment before obtaining the full benefit in terms of decreased risk of coronary heart morbidity and mortality.

Objective: The aim of this study was, on the basis of data from health-care registers, to describe the adequacy of psychopharmacological treatment in suicides. Method: Data on consecutive suicides in a Danish County (Funen) in the period of 1 April 1991–31 December 1995 were identified in the Danish Psychiatric Central Register, the National Patient Register, the National Health Insurance and Odense University Pharmacoepidemiological Database. Results: Twenty-five per cent of the suicides previously hospitalized due to affective disorders and 3% of the suicides without psychiatric hospitalizations at all, received an apparently adequate treatment with antidepressants the month before suicide. Conclusion: The most striking finding was the insufficiency of treatment with antidepressants in the group of suicides without psychiatric hospitalization, in particular in light of the fact that depression is assumed to be present in at least 50% of all suicides.

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: A first step towards subpopulation specific dosages.

Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy but cannot be used in a substantial number of patients. St. John's wort is a herbal antidepressant, which may act via mechanisms similar to the tricyclics. The aim of this study was to test if St. John's wort would relieve painful polyneuropathy. The study design was randomized, double-blind, placebo-controlled and cross-over. Fifty-four patients were assigned to one of the two treatment sequences. The daily dose of St. John's wort was three tablets each containing 900 microg totalhypericin. During the two treatment periods of 5 weeks duration, patients rated constant pain, lancinating pain paroxysms, touch-evoked pain and pain on pressure by use of 0--10 point numeric rating scales. Forty-seven patients -- 18 diabetics and 29 non-diabetics -- completed the study. There was a trend of lower total pain score (sum of the individual pain scores) on St. John's wort than on placebo (median 14 vs. 15, P=0.05). None of the individual pain ratings were significantly changed by St. John's wort as compared to placebo (P=0.09--0.33). Complete, good or moderate pain relief was experienced by nine patients with St. John's wort and two with placebo (P=0.07). In conclusion, St. John's wort has no significant effect on pain in polyneuropathy.

Duration and discontinuation of treatment are essential issues in drug prescribing. General practitioners (GPs) have to decide on the length of the therapy when writing a prescription and also have the responsibility to inform patients accordingly. In Western countries, an increasing number of therapeutic drug groups are primarily prescribed by the GP [1–3]. Prescription data collected at a national level in Denmark in 2001–2005 [4] showed that more than 90% are dispensed by pharmacies servicing the primary health sector. A fraction of these treatments may have been initiated by hospital clinics or specialists, but the continued control of the treatments is largely the responsibility of the GP. Sometimes an ongoing treatment may prove not to be appropriate any more regardless of the time and place of initiation [5], [6]. The decision to stop treatment most often has to be taken by the GP. If unnecessary treatments are continued it may lead to for example polypharmacy, side effects and unnecessary expense. Optimal decisions on duration and discontinuation of drug therapies require that the GP has access to relevant and precise information on the subject. This information should in principle be evidence-based, i.e. founded on scientific data from randomized controlled trials. One might expect such information to be an integral part of national and international textbooks dealing with drug therapies as well as review articles and guidelines in the different fields of therapeutics. However, in many fields of drug therapy explicit recommendations concerning duration of therapy based on appropriate scientific documentation appear to be sparse or non-existent. Therefore we decided to examine the problem more systematically. We evaluated the recommendations given in six internationally well-reputed textbooks dealing with drug therapy: three textbooks on clinical medicine [7–9], two textbooks on clinical pharmacology and therapeutics [10], [11], and one book with review articles on evidence for existing therapies in healthcare [12]. Each book was assessed with regard to recommendations given for some of the drugs typically initiated in general practice (Table I). For a classification of the recommendations given concerning duration and treatment, six categories were defined: No text on drug/indication. No mention of time limitations or optimal duration of therapy. Mention of possible time limitation, but no mention of optimal length of therapy, or only vague suggestions. Included mention of possible long-term adverse effects, drug dependence, loss of effect, etc. Specific recommendations for duration of therapy. Specific indication that the drug therapy is considered lifelong. Diagnostic discontinuation: Indication that therapy usually is lifelong, but that discontinuation may be recommendable to exclude false indication or recovery. Table I. Drug therapy initiated in general practice: Textbook recommendations on duration and discontinuation of therapy. The evaluations were carried out by two of the authors. Divergences were resolved through discussion with the third author. We found good agreement on the ratings and all differences were small and easily resolved by re-examinations of the texts and discussion. Table I shows the number of books for each scoring category (A–F). There was generally good agreement between the different books on the scoring for each drug/indication. Analyses of ratings for individual books revealed no consistent differences between books or types of books (clinical medicine vs. clinical pharmacology and therapeutics). Apart from being short of two of the evaluated drug/indications (score: A), BMJ Clinical Evidence [6] did not differ significantly from the other books. Specific recommendation on duration (score D) was only a general feature for a few drug treatments/indications: anti-ulcer therapy largely linked to the Helicobacter pylori eradication scheme, antimycotics, antibiotics, anti-viral therapy, and antidepressants. For drug-treatment/indications generally considered lifelong we only found one example in one textbook where this was explicitly indicated and in one other case diagnostic discontinuation was suggested. Explicit discussion of the treatment's duration was with a few exceptions only found for short-term regimens and nearly absent for therapies generally considered “chronic”. The textbooks investigated were selected on the basis of their general, international esteem and popularity, but the selection was indeed subjective. Other textbooks, international or national, could have a more practical approach to drug treatment per se and therefore give more specific advice. However, the homogeneity in our findings between the different books investigated was striking and supports the view that the results may be generalizable. The presence or absence of specific recommendations may reflect the level of underlying clinical evidence as typically obtained from randomized controlled trials (RCTs). The frequent, specific recommendations for antimicrobial treatments may thus reflect the fact that duration of treatment is often an explicitly tested variable in RCTs in this field [13–16]. On the other hand, duration of treatment has not been addressed as a primary variable in RCTs on antisecretory medication if Helicobacter pylori eradication schemes are disregarded and classified as antibiotic treatment [17–20]. For antidepressants four out of six textbooks gave specific recommendations on duration despite the fact that a literature search yielded only one original study with duration of treatment as a primary variable [21]. The recommendations given in the literature appear generally to be based on theoretical and clinical considerations [22–24]. As to the presumed “lifelong” treatments, such as lipid-lowering drugs, the general, often implicit recommendation in the literature is that once started the treatment should be lifelong, although little or no direct, hard evidence for the appropriateness of this strategy exists [25–28]. The inclusion of duration as a primary variable in RCTs on presumed lifelong treatments (lipid-lowering drugs, antihypertensives, antidiabetics, antiepileptics, etc.) may pose insurmountable clinical and ethical problems. The evidence must therefore often be sought from less strong data, such as observational studies, epidemiological research etc. However, discontinuation may prove to be possible [29]. It is our opinion that duration of drug therapy has received relatively little attention in the relevant literature, from RCTs to major textbooks. However, for the GP, with the primary responsibility for the vast majority of drug therapies, guidance concerning duration and discontinuation of drug treatment is indispensable. We hope more attention is paid to this issue in the future at all levels: the conduct of RCTs, meta-analyses, reviews, textbooks, guidelines, and regulatory.

In contrast to out-patients, hospitalized depressed patients have been reported to respond better to tricyclic antidepressants (TCAs) than to selective serotonin reuptake inhibitors (SSRIs) and moclobemide. This may be due to differences in the type of patients included in the trials. The hypothesis that hospitalized depressed patients have a different symptom profile to out-patients was tested by comparing 352 patients from three in-patient studies with 581 patients from three out-patient studies conducted in Denmark during the period 1980-1992. All patients had major depression and were evaluated using the Hamilton Depression Scale. The full version of the Newcastle Diagnostic Rating Scale (1965) was applied to 443 of the patients. In-patients were characterized by higher scores on the items 'depressed mood', 'suicidal impulses', 'work and interest (reduced)', 'retardation', 'distinct quality of depression', 'weight loss', 'feeling of guilt' and 'nihilistic delusions', and by lower scores on the items 'somatic complaints', 'hypochondriasis', 'psychological stressors' and 'anxiety'. In total, 76% of the in-patients and 40% of the out-patients had melancholic/endogenous depression. These findings may explain why TCAs are superior to SSRIs and moclobemide in hospitalized patients, since other data indicate that TCAs seem to be the most effective treatment for the melancholic/endogenous subtype.

Objective: Sumatriptan is highly efficacious in aborting acute attacks of migraine. Owing to recent reports of misuse of sumatriptan, we performed a study of its use in a Danish population.

In a randomized, placebo-controlled, double-blind, cross-over study, the hypoalgesic effect of a single oral dose of 100 mg imipramine was investigated in 12 healthy volunteers. Test procedures performed before, 3, 6, and 9 h after medication included determination of (1) pain detection and tolerance thresholds to heat and pressure; (2) the thresholds of quadriceps femoris muscle withdrawal reflex to single and repeated electric stimulation of the sural nerve; (3) amplitude of the reflex evoked by 1.5 times the premedication reflex threshold; and (4) continuous pain rating during the cold pressor test. Imipramine significantly increased pain tolerance thresholds to heat (P = 0.03) and pressure (P = 0.01), and both the psychophysical pain tolerance threshold and the reflex threshold to single electric stimulation (P = 0.02 and P = 0.03, respectively). On the repeated stimuli, which consisted of 4 pulses given at 3 Hz, imipramine induced a significant increase in the threshold at which the pain summated through the stimulation series (P = 0.03), whereas the increase in the threshold at which the reflex summated was not significant (P = 0.09). Pain detection thresholds to heat and pressure, the amplitude of the reflex to single suprathreshold stimulation, and pain ratings during the cold pressor test were unaltered by imipramine. It is concluded that imipramine has a differential hypoalgesic effect on different human experimental pain tests. This provides new possibilities of assessing the differential effect of different tricyclic antidepressants on different pain modalities and intensities.

Fluoxetine was developed as an antidepressant drug. It is more effective than placebo, but a dose-effect relation has not been established. Fluoxetine is almost as effective as tricyclic antidepressant drugs, but the available studies do not allow accurate comparisons. Fluoxetine may be less effective than tricyclic antidepressant drugs for the treatment of inpatients with severe melancholic depression, and it should not be the first choice of a drug for them. Fluoxetine may be most appropriate for patients with moderate depression who can be treated as outpatients. If there is little improvement after treatment for four to six weeks, an alternative treatment should be offered. Fluoxetine does not have the anticholinergic, hypotensive, and sedative effects of tricyclic antidepressant drugs and has no particular cardiovascular effects; overdoses do not cause serious toxic effects. Nausea, anorexia, insomnia, and nervousness--the most common side effects--may be controlled with a careful adjustment to the dose. Clinically important drug interactions may occur with monoamine oxidase inhibitors, tricyclic antidepressant drugs, and other drugs. The published data on the antidepressant effect of fluoxetine do not fully explain its popularity. One may speculate that fluoxetine has psychobiologic effects not strictly related to the biology of depression and that it acts primarily as a mood- or affect-modulating agent.

Objective To investigate to what extent the primary depression subtype atypical depression can predict differential outcome of the mono-amino-oxidase inhibitor (MAO-I) moclobemide and the tricyclic antidepressant clomipramine in the Danish University Antidepressant Group Study (DUAG). Methods In a randomised, double blind trial, a total of 117 patients with major depression were treated over 6 weeks with either 400 mg moclobemide or 150 mg clomipramine. A baseline principal component analysis (PCA) was performed to identify atypical symptoms on the combined depression scales (Hamilton Depression Scale (HAM-D 17 ) and the Quantitative Scale for Atypical Depression (QSAD)). The primary outcome scale was the subscale HAM-D 6 which contains the pure items of depression. Results PCA identified two items with loadings opposite to the other depression items within HAM-D 17 and QSAD, namely increased duration of sleep and increased appetite (atypical neurovegetative symptoms). Patients with a positive score at baseline on these items were classified as having atypical depression. In total 13 patients were classified as having atypical depression. Within this group of patients 8 received clomipramine and 5 patients received moclobemide. At endpoint the moclobemide treated patients had a significantly better response than the clomipramine treated (P = 0.036), effect size 1.42, when using HAM-D 6 as outcome. However, in the 104 patients classified as having typical depression clomipramine was superior to moclobemide (P = 0.034), effect size 0.47. Limitations The number of patients with atypical neurovegetative symptoms was very small and no placebo arm was included. Conclusions It is very important to screen for atypical depression (increased duration of sleep/increased appetite) in the acute therapy of patients with major depression. Our results add to the body of evidence that monoamine oxidase inhibitors are superior to tricyclic antidepressants in this sub-group of patients.

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.

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.

The present study was designed to evaluate possible pharmacokinetic and pharmacodynamic interactions between buspirone administered repeatedly and triazolam given acutely. Ten healthy male volunteers participated in the study and received 0.25 mg of triazolam orally after a one-week pretreatment with either placebo or buspirone 5 mg t.i.d. The study design was double-blind and crossover, the subjects receiving two times triazolam after the random administration of buspirone or placebo, each treatment period being separated by a washout period of 1 week. Plasma triazolam concentrations were measured by a radio-receptor assay using 3H-flunitrazepam as radioligand. Psychomotor effects of triazolam were measured through subjective self rating scales and various cognitive tests exploring concentration, memory and psychomotor skills. Overall, the results of the study failed to demonstrate any significant difference in triazolam subjective or objective effects as well as in triazolam plasma concentrations after a one-week pretreatment with either placebo or buspirone 15 mg daily. They do suggest that clinically relevant interactions are unlikely to appear when buspirone at moderate dosage is co-prescribed with acute doses of triazolam, though these data do not exclude the possibility of pharmacokinetic interactions between the two drugs. Finally our data also suggest the need for more specific studies in order to demonstrate a possible improvement of psychomotor functions after buspirone administration.

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.

Summary 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.

The pattern of adverse drug reactions in elderly is both quantitatively and qualitatively different from that in younger patients. This relates to age-associated changes in physiology, pharmacodynamics and pharmacokinetics. The combination of several risk factors including the use of several drugs concurrently is of special importance in the elderly. Extreme pharmacokinetic variations due to genetic polymorphism in drug action, may, although not in itself age-related, cause particular problems in the elderly. The best-studied drug oxidation polymorphism, related to the model substances sparteine and debrisoquine, is important for several types of drugs, including tricyclic antidepressants, several neuroleptics and several other types of drugs. Sparteine/debrisoquine-poor metabolizers will with standard doses of tricyclic antidepressants or neuroleptics develop very high steady-state blood levels, and this may cause particular problems in the elderly. There are several examples of how the genetic polymorph...

Risk factors in antidepressant therapy can be related to concurrent conditions such as medical illness, other drug therapy and risk of drug-drug interactions, high age and particular features such as genetic polymorphism in drug oxidation, which is particularly important for antidepressants. Adverse events such as suicidal acts, overdose and rare serious reactions represent problems for the treating clinicians and the decision-makers in industry and regulatory bodies.

After an initial placebo week, 37 depressed inpatients were treated with the fixed dose of 75 mg clomipramine b.d. A sparteine test was carried out during the placebo period and again during the second week of active therapy. Blood for drug assay was collected at the end of the inter-dose interval in the (morning) at weekly intervals. Clomipramine and four metabolites (desmethylclomipramine, didesmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine) in plasma were assayed by reversed phase HPLC. The clomipramine and desmethylclomipramine steady-state plasma levels varied by factors of 11 and 9, respectively, and the clomipramine/8-hydroxyclomipramine and desmethylclomipramine/8-hydroxydesmethylclomipramine ratios both varied by 7-fold. During the placebo week, 36 patients were phenotyped as extensive metabolizers (EM) (metabolic ratio, MR, 0.1-2.0), and one patient was phenotyped as a poor metabolizer (PM) (MR > 300). During clomipramine treatment, one patient changed phenotype from EM to PM (MR = 140). In the EM, the median of the MR increased from 0.4 to 2.3. There was a statistically significant correlation between the MR before and during clomipramine treatment, even when the PM was excluded. Neither the steady-state plasma clomipramine levels nor the clomipramine/desmethylclomipramine ratios showed a significant correlation with the MR. In contrast, the desmethylclomipramine and didesmethylclomipramine steady-state levels and the desmethylclomipramine/8-hydroxydesmethylclomipramine and clomipramine/8-hydroxyclomipramine ratios showed a significant positive correlation with the MR. The PM had the highest steady-state plasma desmethylclomipramine level and the highest desmethylclomipramine/8-hydroxydesmethylclomipramine ratio. These correlation coefficients (rs) were generally increased when the correlation analyses were based on the MR obtained during clomipramine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the possible role of endogenous opioid peptides in the action of imipramine and paroxetine in painful diabetic neuropathy, beta-endorphin concentrations in plasma were measured in 20 patients during a double-blind, placebo-controlled randomized three-way crossover trial. Despite a significant reduction in neuropathy symptoms during both imipramine and paroxetine treatment, the beta-endorphin level was unaltered throughout the study. The plasma concentration of beta-endorphin was not related to plasma drug concentrations. Thus, this study does not provide evidence of a role of endogenous opioid peptides in the mechanism of action of imipramine and paroxetine in painful diabetic neuropathy.

A single-blind dose-escalation study with the selective serotonin reuptake inhibitor paroxetine was conducted in 19 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by self-rating using visual analog scales. After an initial placebo period, paroxetine doses were increased from 10 mg/day in 10 mg steps, until the dose was 30-70 mg/day. In all except four patients, there was a marked relief of symptoms. Plasma concentrations of paroxetine above 300-400 nM were required to insure maximal relief in the majority of patients responding on paroxetine, but a considerable interindividual variation was observed (10-800 nM, median of 195 nM). The therapeutic effect appeared to increase gradually as the plasma concentration increased. The great interindividual variation in the pharmacokinetics of paroxetine was confirmed, but as the effect is maximal within approximately 1 week, and the drug is nontoxic, it may be clinically feasible simply to titrate the dose from 20 mg/day until the maximal effect is achieved. However, it is advised that titration to an effect, in diabetic neuropathy using doses above 50 mg/day, be undertaken with care as there is limited experience with doses above this level in any population. The beneficial effect of paroxetine appeared to be maintained unaltered during an additional 1 month open-label treatment on optimal paroxetine doses.

The oxidation of sparteine and mephenytoin was examined in a group of subjects living in Greenland: 300 in East Greenland and 171 in West Greenland. The distributions of the ratio between the chromatographic peak areas of S- and R-mephenytoin in the urine, the S/R ratio was clearly bimodal in both populations. Thus 9.3% of the East Greenlanders had S/R ratios of 0.9 or more and were phenotyped as poor metabolizers of mephenytoin. In the West Greenlanders, 2.9% of the sample had S/R ratios of 0.90 or more and were accordingly phenotyped as poor metabolizers. The intraethnic difference with regard to the frequency of the mephenytoin poor metabolizer is probably attributable in part to a much higher proportion of admixed Caucasian genes in the West Greenlanders than in the East Greenlanders. In both the East and the West Greenlanders, the sparteine metabolic ratio displayed marked interindividual differences without a dear bimodal distribution. Poor metabolizers arbitrarily defined as subjects with an metabolic ratio of 20 or more made up 3.3% of the East Greenlanders and 2.3% of the West Greenlanders, but the difference between the two groups was not statistically significant.

Three hundred and sixty-six consecutive patients admitted to a department of cardiology were evaluated for drug events as a cause of admission. The drug events considered were adverse drug reactions (ADR) and dose-related therapeutic failures (DTF). 'Definite' or 'probable' drug events accounted for 15 admissions (4.1%, 95% confidence limits 2.3-6.7%), of which eleven were ADR and four were DTF. With the inclusion of six 'possible' drug events, the rate of drug-related hospitalizations (DRH) was 5.7%. DRHs were characterized by a preponderance of acute admissions and elderly patients. Hypokalaemia (less than 3.5 mM) was observed in 27 (16%) patients receiving diuretics, and could be related to four cases of arrhythmias (two 'probable' and two 'possible' ADR). The average serum potassium level was similar in diuretic treated patients with or without drugs to counteract hypokalaemia, irrespective of the drugs chosen. Among the 15 'definite'/'probable' DRHs, five were considered to be due to an error in prescription, and a further five cases were judged to have been avoidable had appropriate measures been taken by prescribing physicians. A DRH educational intervention programme should primarily deal with non-compliance or with prescription of diuretics or digoxin, since these problems constitute the majority of cases of DRH. No specific group of doctors could be targeted as responsible for DRH, avoidable or not.

Three hundred and thirty‐three consecutive patients in a medical ward were evaluated in a high‐intensity monitoring scheme for drug events as a cause of hospitalization. Taking into consideration only ‘definite’ and ‘probable’ drug events, we found 36 cases (10.8%) of all admissions to be drug‐related hospitalizations (DRH). Of these, 8.1% were adverse drug reactions and 2.7% were therapeutic failures due to ineffective dosage. In 8 cases (2.4%) the drug event could definitely have been avoided, and a further 13 cases (3.9%) were considered to have been potentially avoidable if appropriate measures had been taken by the health service. In 19 cases (53%) the referring physician was unaware of the drug‐related problem. Those patients admitted because of a drug event were taking significantly more drugs than other individuals. The avoidable drug events pointed to the primary health care physicians as the appropriate targets for preventive measures in terms of intensified drug education. The study demonstrated that a reliable estimate of the DRH rate requires active data collection by a qualified health service worker in close collaboration with the patient's family doctor in cases of suspected DRH. 1990 Blackwell Publishing Ltd

The scientific literature on tricyclic antidepressants contains few studies on the dose-effect relationship, and this aspect of the treatment has for many years been given little attention. However, recent reviews point out inadequate dosing as an important factor in "drug resistant depressions." Tricyclic antidepressants have a narrow therapeutic range and standard doses, which are frequently recommended, will not be therapeutic in some patients and toxic in other patients. Use of flexible dose schemes, which has been customary in clinical trials, carry a considerable risk of underdosing because common side effects occur at subtherapeutic doses. Dosing according to therapeutic effect is not feasible in light of the slow and variable rate of response. Much of the difficulties in establishing a dose-effect relationship appears to be related to the considerable pharmacokinetic variability. The major source of this variability is the genetic polymorphism related to the sparteine/debrisoquine oxygenase. For some of the tricyclic antidepressants, a concentration effect relationship has been established, but almost exclusively on the basis of retrospective studies. The dose-response problem is particularly important in clinical trials. Apparent differences or equivalence between a new drug and the control therapy thus may entirely be related to differences in doses of the two drugs. For tricyclic antidepressants, the use of flexible dose schedules and poor control of compliance may often lead to underdosing and a response rate below the real potentials of these drugs. Underdosing combined with a high rate of placebo response will increase the type 2 error risk considerably and may ultimately lead to the introduction of drugs that are less effective than the classical drugs.

To evaluate the impact of an intensive pharmaceutical care campaign targeting inappropriate use of triptans.Randomized controlled trial.22 community pharmacies in the County of Funen, Denmark.A total of 1123 triptan users at intervention pharmacies and 1340 at control pharmacies.Intervention pharmacy staff received information on migraine and other types of headache, detection of inappropriate triptan use and other drug-related problems, and techniques for establishing a dialogue with patients. Intervention consisted of a folder and a structured dialogue with the pharmacy staff. The folder included questions aimed at detecting overuse and inappropriate triptan use.Change in average triptan consumption in doses per month measured by means of a prescription database with information on all purchases of reimbursed drugs at the level of the individual patient.Overall, intervention had no statistically significant short-term impact on patients' consumption of triptans either among incident users (intervention/control ratio 1.02; 95% confidence interval 0.95 to 1.12), or among prevalent users (1.02; 0.97 to 1.08). No effects were observed after 6 and 9 months, apart from a possible borderline effect after 9 months among prevalent users with intermediate triptan consumption (0.93; 0.87 to 1.00).The pharmaceutical care campaign did not reduce the use of triptans.

To analyse whether first-time use of antidepressants (incidence) and selection of TCAs (tricyclic antidepressants) versus new-generation drugs are associated with socio-economic status and psychiatric history. We conducted a population-based cohort study using registry data covering Funen County, Denmark. A total of 305,953 adult residents without antidepressant prescriptions 5 years prior to the study period (1998) were included. The 1-year incidence rate of antidepressant prescription (1.7%) increased with age. It was higher in people who were female, less educated, unemployed, those receiving old-age or disability pension, low-income groups, and singles. The proportion prescribed new-generation antidepressants (82%) showed no difference according to socio-economic variables (education, annual income and socio-economic group), but was higher among the young and single. Admission to psychiatric hospital within 4 years prior to the study period was associated with high-incidence rate of antidepressant prescription and overall a preference for the new-generation antidepressants. Socio-economic status did not seem to influence the selection of TCAs versus new-generation antidepressants. Compatible with the general epidemiology of depression, low socio-economic status was associated with a high number of first-time users of antidepressants in the population, and the incidence rate increased with age.

The effect of lipid-lowering drugs (LLDs) on coronary heart disease is well documented, particularly in patients with established ischaemic heart disease. However, intensity of the use of these drugs is low. The aim of this linkage study was to analyse the use of serum cholesterol measurements and LLDs among patients with a history of myocardial infarction (MI) in a Danish population.Information on serum cholesterol values was retrieved from the hospital's Department of Clinical Chemistry for all patients from the Odense municipality and four surrounding municipalities (213,868 inhabitants) hospitalised at Odense University Hospital for MI between 1994-1997. Information on LLD use was obtained from a prescription database. Only patients alive at discharge were included in the investigation. The total observation period was from 1993-1998.In all, 1,018 patients were eligible for observation and 39% of the patients who met the criteria for LLD reimbursement (MI and serum cholesterol5.4 mmol/L) started treatment. Relatively more males than females and relatively more patients under the age of 70 years were treated. Patients above the age of 70 years were prescribed these drugs at a slower rate.More attention to the insufficient use of lipid-lowering drug treatment in patients with established coronary heart disease is needed.

The aim of this study was, on the basis of data from health-care registers, to describe the adequacy of psychopharmacological treatment in suicides.Data on consecutive suicides in a Danish County (Funen) in the period of 1 April 1991-31 December 1995 were identified in the Danish Psychiatric Central Register, the National Patient Register, the National Health Insurance and Odense University Pharmacoepidemiological Database.Twenty-five per cent of the suicides previously hospitalized due to affective disorders and 3% of the suicides without psychiatric hospitalizations at all, received an apparently adequate treatment with antidepressants the month before suicide.The most striking finding was the insufficiency of treatment with antidepressants in the group of suicides without psychiatric hospitalization, in particular in light of the fact that depression is assumed to be present in at least 50% of all suicides.

Objective: The effect of lipid-lowering drugs (LLDs) on coronary heart disease is well established. However, their utilisation is often suspected to be too low. The aim of this study was to describe the epidemiology of LLD use with special emphasis on the development of utilisation over a 6-year period in a Danish population. Methods: For all people who purchased LLDs from 1993 to 1998 in Funen County, all prescriptions for LLDs and co-medication with cardiovascular and anti-diabetic drugs were retrieved from Odense University Pharmacoepidemiologic Database (OPED). Results: During the study period, LLD use increased nearly exponentially. In 1998, statins accounted for 95% of the total LLD consumption. The incidence increased markedly around the time of the publication of the Scandinavian Simvastatin Survival Study (4S). Only 3% of the statins were purchased without reimbursement. The female/male ratio was 0.69 and the median age was 60 years. General practitioners issued 73% of the total number of LLD prescriptions, and 55% of the treatments were initiated in general practice. A larger fraction of females and elderly started treatment in general practice. About 40% of the treatments were hospital initiated, and about one-third were followed up in general practice within the first year. Conclusions: Over the 6 years studied, utilisation of LLDs approached a level that may correspond to the current guideline recommendations. Compliance with guidelines should, however, be studied by following people with coronary heart disease.

This review aimed to provide distinct dose recommendations for antidepressants based on the genotypes of cytochrome P450 enzymes CYP2D6 and CYP2C19. This approach may be a useful complementation to clinical monitoring and therapeutic drug monitoring.Our literature search covered 32 antidepressants marketed in Europe, Canada, and the United States. We evaluated studies which had compared pharmacokinetic parameters of antidepressants among poor, intermediate, extensive and ultrarapid metabolizers.For 14 antidepressants, distinct dose recommendations for extensive, intermediate and poor metabolizers of either CYP2D6 or CYP2C19 were given. For the tricyclic antidepressants, dose reductions around 50% were generally recommended for poor metabolizers of substrates of CYP2D6 or CYP2C19, whereas differences were smaller for the selective serotonin reuptake inhibitors.We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.

To evaluate the effects of postal feedback with clinically relevant data on general practitioners' prescribing compared with feedback with aggregate data on prescribing patterns of asthma drugs.The study was a randomised, controlled trial. The general practitioners (GPs) in the County of Funen, Denmark (292 GPs representing 178 practices) were randomised to one of three groups receiving different forms of prescriber feedback. The first group received detailed and clinically relevant data on asthma drug prescribing patterns and a guideline statement. These data included tables with counts of asthma patients following classification of each individual's consumption of inhaled beta2-agonists and use of inhaled steroids. The second group received aggregate data on asthma drug prescribing patterns and a guideline statement, and the third group received feedback on an unrelated subject and served as control for the other groups. Each GP received prescriber feedback three times within a 6-month period. The last two letters with prescriber feedback had updated information with the purpose of showing changes in prescribing patterns. Effects were followed for a period of 1 year. The main outcome measures were change in fraction of asthmatics treated with inhaled steroids and incidence rate of treatment with inhaled steroids.The three groups had similar baseline characteristics. None of the two types of feedback on prescribing of asthma drugs had a statistically significant impact on GPs' prescribing patterns.Mailed prescriber feedback of detailed and clinically relevant data with a guideline statement, without revealing patient identities, has little or no impact on prescribing patterns.

In Oslo, traffic has been one of the dominating sources of air pollution in the last decade. In one part of the city where most traffic collects, two tunnels were built. A series of before and after studies was carried out in connection with the tunnels in use. Dispersion models were used as a basis for estimating exposure to nitrogen dioxide and particulate matter in two fractions. Exposure estimates were based on the results of the dispersion model providing estimates of outdoor pollutant concentrations on an hourly basis. The estimates represent concentrations in receptor points and in a square kilometre grid. The estimates were used to assess development of air pollution load in the area, compliance with air quality guidelines, and to provide a basis for quantifying exposure-effect relationships in epidemiological studies. After both tunnels were taken in use, the pollution levels in the study area were lower than when the traffic was on the surface (a drop from 50 to 40 micrograms m-3). Compliance with air quality guidelines and other prescribed values has improved, even if high exposures still exist. The most important residential areas are now much less exposed, while areas around tunnel openings can be in periods exposed to high pollutant concentrations. The daily pattern of exposure shows smaller differences between peak and minimum concentrations than prior to the traffic changes. Exposures at home (in the investigation area) were reduced most, while exposures in other locations than at home showed only a small decrease. Highest hourly exposures are encountered in traffic.

Aim: The aim of the present study was to analyse the utilisation of antidepressants (ADs) and to compare the utilisation of the various ADs with special reference to duration of treatment courses. Method: From the Odense Pharmacoepidemiologic Database (OPED), all users of and prescriptions for ADs in the County of Funen, Denmark (about 470,000 inhabitants), were identified for each year from 1992 to 1997 (6 years). Duration of treatment courses was calculated for the first incident period of continuous use of one AD and was compared for the various ADs using Kaplan-Meiers survival statistics with log rank tests. Continuous use was defined as use of a minimum of one tablet per day. Furthermore, the proportion of users presenting only one prescription was determined for each AD. Results: In total, 37,598 patients presented 392,524 prescriptions during 1992–1997. The 1-year prevalence rose from 2.1% to 4.1% in 1997 and the incidence was 1.3% in 1997. The 1-year prevalence increased with age up to 16.5% in 1997 for patients aged 90 years or older. Citalopram was the most-used AD, but there were still a considerable number of patients commencing treatment with TCAs in 1997. Median duration of treatment courses was 196 days for TCAs versus 120 days for SSRIs (P

Background Tricyclic antidepressants relieve neuropathic pain, and the analgesic properties of tricyclic antidepressants are substantiated in human experimental pain models. It has been speculated that drugs with a selective inhibition of presynaptic reuptake of both serotonin and noradrenaline could have an analgesic effect comparable to the analgesic effect of tricyclic antidepressants. Objective Our objective was to evaluate the analgesic effect of the serotonin-noradrenaline reuptake inhibitor venlafaxine in human experimental pain models. Method The study was carried out as a randomized, placebo-controlled, double-blind, crossover experiment that included 16 healthy volunteers. A 37.5-mg dose of venlafaxine was given orally 4 times with 12-hour intervals, and pain tests were performed before and 3 hours after the second and fourth doses. Pain tests included the determination of pain detection and tolerance thresholds to pressure, pain detection and tolerance thresholds on single electrical transcutaneous stimulation of the sural nerve, pain temporal summation on repetitive electrical sural nerve stimulation, and pain experienced during the cold pressor test. Results Venlafaxine increased thresholds for pain tolerance after single electrical stimulation (P = .005) and pain summation (P = .01) on repetitive stimulation but did not alter the thresholds for pain detection after single electrical sural nerve stimulation. Venlafaxine did not alter pain experienced during the cold pressor test or increase the pressure pain thresholds. Conclusion Venlafaxine increases the pain tolerance threshold to electrical sural nerve stimulation and the threshold at which pain increases (pain summation). The impact of venlafaxine on pain summation in this experimental pain model on repetitive stimulation may indicate a potential analgesic effect for clinical neuropathic pain. Clinical Pharmacology & Therapeutics (2001) 69, 245–251; doi: 10.1067/mcp.2001.114873

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that have been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have been previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we describe pyrimidine-triones as a completely new class of metalloprotease inhibitors. While the pyrimidine-trione template is used as the zinc-chelating moiety, the substituents have been optimized to yield inhibitors comparable in their inhibition efficiency of matrix metalloproteinases to hydroxamic acid derivatives such as batimastat. However, they are much more specific for a small subgroup of MMPs, namely the gelatinases (MMP-2 and MMP-9).

The hypoalgesic effect of single oral doses of 100 mg imipramine and 125 mg codeine was evaluated in a randomised, placebo-controlled, double-blind, 3-way cross-over experiment including 18 healthy volunteers. Pain tests were performed before and 90, 180, 270, 360 and 450 min after medication. The tests included determination of pain tolerance thresholds to pressure, pain detection/tolerance thresholds to single electrical sural nerve stimulation and pain summation at tolerance threshold to repetitive electrical sural nerve stimulation (temporal summation) and pain experienced during the cold pressor test, rated as peak pain intensity, pain average intensity and discomfort. Compared to placebo, imipramine significantly increased pressure pain tolerance threshold (P = 0.03) and increased pain tolerance threshold (P = 0.05) and pain summation threshold (P = 0.03), but not pain detection threshold to electrical stimulation. Imipramine did not cause significant changes in pain perception during the cold pressor test. Codeine significantly increased pressure pain tolerance threshold (P = 0.02), pain detection (P = 0.04) and pain tolerance threshold (P = 0.01) and pain summation threshold (P = 0.02) to electrical stimulation. In addition, codeine reduced the pain experienced during the cold pressor test (P = 0.04-0.003). It is concluded that both imipramine and codeine inhibit temporal pain summation, whereas only codeine reduces cold pressor pain. Pain summation may be a key mechanism in neuropathic pain. Imipramine has a documented effect on such pain conditions on temporal summation. The present study showed that codeine also inhibits temporal summation, which is in line with the clinical observations indicating that opioids relieve neuropathic pain.

Therapeutic Drug Monitoring (TDM) is based on a series of theoretical assumptions, a clinical pharmacological rationale, scientific documentation and a practical implementation, respecting the theoretical and scientific basis. The clinical pharmacological rationale for TDM; a pharmacokinetic variability exceeding therapeutic index and dose titration on the basis of clinical or paraclinical measurements not being feasible, limits TDM to a minor fraction of all drugs available. The theoretical assumption that blood concentration measurements reflect/predict the tissue/receptor concentration and the clinical endpoints, requires several points to be considered such as concentration fluctuations, protein binding, active metabolites, etc. A relatively constant ratio between blood and tissue/receptor concentration is generally assumed, but the important role of transporter proteins, with inter- and intraindividual variability due to polymorphisms, inducers and inhibitors seriously challenge this basic assumption. Concentration–effect relationships concerns groups of patients and indicate the probability of a given response (therapeutic/toxic) at a given concentration. Dose–effect and concentration–effect studies of drugs like digoxin, lithium and antidepressants have shown that the dose–effect or concentration–effect curves for therapeutic effect and tolerability are flat and overlapping. Dose–effect studies, now standard in drug development, represent a unique possibility to examine dose–concentration–effect relationships of new drugs.

Prescription databases are indispensible in drug safety research and surveillance. For suspected rare serious adverse drug reactions, the confirmation and quantitative risk assesment requires proper epidemiological studies. Often prescription databases provide the information on drug exposure for such studies. Abberant drug utilization in terms of overuse, underuse, polypharmacy etc. may be a threat to the health of the patient, and these aspects can best be studied by prescription databases. In cases of international drug safety alerts, prescription databases may provide information required for rational actions to be taken.