Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

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.

The predictive validity of atypical neurovegetative depressive symptoms identified by the first principal component in the DUAG trial of moclobemide versus clomipramine.

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.

Acute and continuation therapy in unipolar depression: observations from the run-in phase of a maintenance trial.

OBJECTIVE: The aim of the study was to analyze treatments and outcome in depressed patients. METHOD: Patients with recurrent depressive disorder (n = 289), recruited for a prophylaxis study, were followed up in hospital settings for 6 months with diagnostic and depression ratings at baseline and monthly depression ratings. Data on psychotropic drugs were retrieved from hospital case records. Independent associations between baseline, treatment and outcome variables were examined by logistic regression models. RESULTS: Depressive symptoms subsided gradually. After 6 months, 21% had dropped out, 43% were rated as remitted (HAM-D-17 <8) and 8% had not responded (HAM-D-17 >15). Patients once remitted rarely relapsed (<5%). All patients received antidepressant drugs, half of them more than one (2-4) as well as other psychotropic drugs. Patients responding poorly received more frequently multiple antidepressants, tricyclic antidepressants, hypnosedatives, lithium and/or antipsychotics. CONCLUSION: The 6-month outcome was generally poor. Choice of treatment appeared at least partly to be determined by the therapeutic outcome.

Socio-economic inequalities in first-time use of antidepressants: a population-based study.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial.

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.

Changes in the utilisation of lipid-lowering drugs over a 6-year period (1993-1998) in a Danish population.

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 antidiabetic 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.

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

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans.

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.

Are there differences in the use of selective serotonin reuptake inhibitors and tricyclic antidepressants? A prescription database study.

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 < 0.0001). Duration of treatment courses increased with age. The proportion of users presenting only one prescription was 22% for the SSRIs versus 33% for tricyclic antidepressants (TCAs). CONCLUSION: This study showed that the use of ADs continues to increase because of the increase in the use of the new ADs. There was, however, still a considerable number of patients who started on TCA treatment in 1997. For repeated prescriptions, TCAs were used for longer times than SSRIs. In the very old, there was an apparently inappropriate high use of ADs.

The analgesic effect of codeine as compared to imipramine in different human experimental pain models.

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.

Psychopharmacological treatment and psychiatric morbidity in 390 cases of suicide with special focus on affective disorders.

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.

Contacts to the health care system prior to suicide: a comprehensive analysis using registers for general and psychiatric hospital admissions, contacts to general practitioners and practising specialists and drug prescriptions.

OBJECTIVE: The purpose of this study was to describe suicides' contacts with various parts of the health-care system. METHOD: Data on 472 people who committed suicide in a Danish County (Funen) in the period of April 1 1991 to December 31 1995 were searched in the Danish Psychiatric Central Register, the National Patient Register, the National Health Insurance and Odense Pharmacoepidemiologic Database. RESULTS: In total, 97.5% of the suicides were recaptured in at least one of these registers. Forty-two per cent had been hospitalized in psychiatric departments. Within the last month before death, 66% consulted a general practitioner, 13% and 7%, respectively, were discharged from a psychiatric hospital and general hospital. CONCLUSION: The registers used provided a comprehensive registry-based description of suicides' contacts with the health-care system. The most prominent features were the high prevalence of psychiatric morbidity and the high rate of contacts with GPs close to suicide.