Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).

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.

Intensive community pharmacy intervention had little impact on triptan consumption: a randomized controlled trial.

OBJECTIVE: To evaluate the impact of an intensive pharmaceutical care campaign targeting inappropriate use of triptans. DESIGN: Randomized controlled trial. SETTING: 22 community pharmacies in the County of Funen, Denmark. SUBJECTS: A total of 1123 triptan users at intervention pharmacies and 1340 at control pharmacies. INTERVENTION: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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). CONCLUSION: The pharmaceutical care campaign did not reduce the use of triptans.

Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression: a double-blind, randomised 6-month comparative trial with citalopram.

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.

Early discontinuation of antidepressants in general practice: association with patient and prescriber characteristics.

BACKGROUND: Most antidepressant treatment is initiated and continued in general practice but, despite current guidelines, treatment duration is often short among patients with depression. Discontinuation may, however, be caused by a complexity of factors, but so far research has focused on drug effects, adverse effects and drug regimens. OBJECTIVE: Our aim was to analyse whether early discontinuation of first-time antidepressant treatment in general practice may be predicted by (i) social position and psychiatric history of the patient; and (ii) demography, practice activity and the general prescribing behaviour of the GP. METHODS: Early discontinuation, i.e. that patients do not purchase antidepressants in the 6 months following first prescription, was analysed using established databases. Among patients presenting in 174 general practices in Funen County, Denmark, 4860 adult first-time users of antidepressants were identified (regardless of diagnosis). The inclusion period was January 1998-June 1999. RESULTS: One in three patients did not purchase antidepressants in the 6 months following first prescription, but rates were higher among those prescribed tricyclic compared with new generation antidepressants. Patients' age and sex did not have an influence, but early discontinuation was more frequent among patients of low socio-economic status and patients prescribed in practices characterized by high prescribing rates. No association with psychiatric history was observed. CONCLUSION: Early discontinuation is frequent in general practice, and patients of low social status are at greater risk. Adherence-promoting strategies should pay attention to the high prescribing doctors. Further studies may answer the question of whether the association between doctors' prescribing behaviour and early discontinuation is a feature specific to antidepressants or a more general phenomenon.

Antidepressant drug use in general practice: inter-practice variation and association with practice characteristics.

OBJECTIVE: The use of antidepressants (ADs) has escalated and prompted considerable debate. Many depressed patients go unrecognised or under-treated and the area of indication of the new ADs is widening. The aim of this study was to analyse (i). the variation in general practitioners' prescribing of ADs by comparing with prescribing of other drug groups and (ii). whether the general prescribing behaviour, practice activity and demography are associated with the AD prescribing. METHODS: Analysis of AD prescribing patterns among 174 general practices (93.5%) in the County of Funen, Denmark. Age- and sex-standardised 1-year incidences and prevalences of AD prescribing for patients listed were calculated using individual prescription data from Odense University Pharmacoepidemiologic Database. Data about health services and practice demography were obtained from the Health Insurance Register. The variation in AD 1-year prevalence was compared with other drug groups by a variation index (90%/10% percentile). Univariate linear regression analysis was used to examine associations between practice characteristics and prescribing. RESULTS: The 1-year prevalence of AD prescribing varied sixfold, no more than the prevalence of five other drug groups. Practices with high yearly: general prescribing prevalence, mean number of drugs per medicated patient, number of surgery consultations/100 patients and counsellings/100 surgery consultations showed the highest yearly prevalence of AD prescribing. Single-handed practices had higher AD prescribing rates than partnerships. The relative use of selective serotonin re-uptake inhibitors and other new ADs showed only little variation (10% and 90% percentiles as close as 66-86%), but practices with high 1-year prevalence and incidence most often chose the new ADs. CONCLUSION: Analysis of inter-practice variation showed no extraordinary quality problems with regard to AD prescribing, but does not exclude that there might be problems. The general prescribing pattern of the general practitioners seems essential to their attitude to AD prescribing. The relationship between counselling and prescribing was a feature specific to ADs and deserves further investigation. Quality indicators are needed to understand differences in AD prescribing, and studies based on prescription data have to be supplemented with individual clinical data.

Insufficient use of lipid-lowering drugs and measurement of serum cholesterol among patients with a history of myocardial infarction.

BACKGROUND: 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. METHODS: 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. RESULTS: In all, 1,018 patients were eligible for observation and 39% of the patients who met the criteria for LLD reimbursement (MI and serum cholesterol >5.4 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. CONCLUSIONS: More attention to the insufficient use of lipid-lowering drug treatment in patients with established coronary heart disease is needed.

Hyponatraemia in very old nonhospitalised people: association with drug use.

OBJECTIVE: Hyponatraemia is one of the major problems in geriatric inpatients. However, in nonhospitalised elderly, the preponderance of hyponatraemia and the importance of the effect of drug intake on serum sodium concentrations are little known. This study investigated the prevalence of hyponatraemia in very old nonhospitalised people, controlling for factors that may induce hyponatraemia (especially drug use). METHODS: Data on serum sodium concentration, health and drug use were retrieved for 185 persons aged 92 to 93 years (the 1905 cohort) and 147 persons aged 100 years (the centenarian cohort) participating in two major population-based studies of elderly people in Denmark. Data were analysed by comparing median serum sodium concentrations between users and nonusers of various drugs after controlling for the influence of age, sex, cancer, heart failure, hypothyroidism, renal failure and smoking. Furthermore, the preponderance of drug use in the patients with clinically relevant hyponatraemia was compared with that in persons with normal serum sodium concentrations. RESULTS: Median serum sodium concentration was 140 mmol/L for the centenarians and 141 mmol/L for the 1905 cohort. In total, 19 persons had hyponatraemia (serum sodium concentration < or =134 mmol/L). There was no association between median serum sodium concentration and any of the above-mentioned diseases, or sex or smoking. Of the drugs generally known to cause hyponatraemia, only omeprazole and oral antidiabetic agents were associated with significantly lower median serum sodium concentrations (difference 3 mmol/L). Use of thiazide diuretics was significantly more common than expected in persons with hyponatraemia compared with persons with a normal serum sodium concentration (7 of 19 vs 46 of 270 individuals). Furthermore, the results suggested that digoxin and lactulose might be associated with a lowered median serum sodium concentration. CONCLUSION: This study demonstrates that severe hyponatraemia was rarely seen in a population-based sample of very old persons and that drugs have only a limited influence on serum sodium concentration. The only drug class associated with clinically relevant hyponatraemia was thiazide diuretics, which were used by significantly more persons with hyponatraemia. Furthermore, this study suggests that digoxin and lactulose use is associated with lower serum sodium concentrations in the elderly.

Detailed postal feedback about prescribing to asthma patients combined with a guideline statement showed no impact: a randomised controlled trial.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Why has postal prescriber feedback no substantial impact on general practitioners' prescribing practice? A qualitative study.

OBJECTIVE: To better understand the reasons for lack of impact of sending feedback on prescribing pattern to general practitioners (GPs). METHODS: Semi-structured interviews with GPs who had all participated in intervention studies addressing effects of prescriber feedback. Interviews were audiotaped and fully transcribed. Transcripts were studied repeatedly and coded into categories in order to produce meaningful patterns. RESULTS: None of the GPs believed they altered prescribing practice after they received prescriber feedback. Unsolicited prescriber feedback was perceived as violating the GPs' autonomy. The GPs wanted to decide for themselves what data should be sent to them. Aggregated data were difficult to interpret, and GPs did not regard it as a problem that their practice pattern deviated from that of other practices. There was a mistrust of the validity of data, and the GPs wanted to be able to identify the patients with a need for optimised therapy directly from the information provided in the prescriber feedback. In addition they wanted advice on how to optimise therapy. CONCLUSION: Postal prescriber feedback (not revealing the patients' identities) is not effective because it does not motivate GPs to change nor does it address the barriers to change. Prescriber feedback requested by the GPs may be more effective, however, if it includes identities of inappropriately treated patients combined with relevant advice on how to optimise prescribing.

High persistence of statin use in a Danish population: compliance study 1993-1998.

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.

St. John's wort has no effect on pain in polyneuropathy.

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.

Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers?

It has recently been shown that O-demethylation of the opioid drug codeine to morphine depends on the sparteine/debrisoquine oxygenase (CYP2D6) which in man exhibits genetic polymorphism. Morphine may be an endogenously formed substance in mammalians. Therefore, it may be hypothesized that the final step in an endogenous synthesis of morphine from codeine also depends on CYP2D6. CYP2D6, which is present in the liver and presumably also in the brain, is not expressed in subjects who are poor metabolisers of the sparteine/debrisoquine type. We have determined sensitivity to painful stimuli in 94 extensive metabolisers and 82 poor metabolisers of sparteine in 2 phasic (pain thresholds to heat and pressure) and 1 tonic (cold pressor test) experimental pain model. Extensive and poor metabolisers did not differ significantly in the 2 phasic pain models neither with respect to pain detection nor pain tolerance thresholds. However, for the cold pressor test, peak pain ratings and area under the pain rating-time curve during 2 min were significantly higher in poor than in extensive metabolisers (P = 0.0024 and 0.044). Furthermore, a substantially higher fraction of poor metabolisers prematurely withdrew their hand from the ice water during the cold pressor test due to intolerable pain (32 vs. 18%, P = 0.0545). We conclude that poor metabolisers of sparteine may be less tolerant to tonic pain than extensive metabolisers, and we hypothesize that this may be related to an inherited defect in endogenous synthesis of morphine via CYP2D6 in the brain.

The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms.

The effect of the selective serotonin reuptake inhibitor paroxetine on diabetic neuropathy symptoms was examined in comparison to imipramine and placebo in a randomised, double-blind, cross-over study. Paroxetine was given as a fixed dose of 40 mg/day, while the dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 400-600 nM. Paroxetine significantly reduced the symptoms of neuropathy as measured by both observer- and self-rating, but was somewhat less effective than imipramine. However, patients showing a weaker response to paroxetine than to imipramine had lower plasma concentrations of paroxetine than patients with similar response to the 2 drugs. On imipramine 5 patients dropped out because of intolerable side effects and 4 of 19 patients completing the study reported withdrawal symptoms after discontinuing imipramine. On paroxetine no patients dropped out due to side effects and no withdrawal symptoms were reported. Self-rating showed no depressive symptoms at baseline, and no changes during the study. Neither paroxetine nor imipramine caused changes in objective measures of peripheral nerve function. In conclusion, 40 mg paroxetine/day significantly reduced the symptoms in peripheral diabetic neuropathy, and it was suggested that by dose adjustment on the basis of drug level monitoring, paroxetine may become as effective as imipramine. Paroxetine was devoid of the often disturbing autonomic side effects limiting the use of imipramine in several patients.