Effect of educational outreach on general practice prescribing of antibiotics and antidepressants: a two-year randomised controlled trial.

OBJECTIVE: Prescribing of broad spectrum antibiotics and antidepressants in general practice often does not accord with guidelines. The aim was to determine the effectiveness of educational outreach in improving the prescribing of selected antibiotics and antidepressants, and whether the effect is sustained for two years. DESIGN: Single blind randomized trial. SETTING: Twenty-eight general practices in Leicestershire, England. INTERVENTION: Educational outreach visits were undertaken, tailored to barriers to change, 14 practices receiving visits for reducing selected antibiotics and 14 for improving antidepressant prescribing. MAIN OUTCOME MEASURES: Number of items prescribed per 1000 registered patients for amoxicillin with clavulanic acid (co-amoxiclav) and quinolone antibiotics, and average daily quantities per 1000 patients for lofepramine and fluoxetine antidepressants, measured at the practice level for six-month periods over two years. RESULTS: There was no effect on the prescribing of co-amoxiclav, quinolones, or fluoxetine, but prescribing of lofepramine increased in accordance with the guidelines. The increase persisted throughout two years of follow-up. CONCLUSION: A simple, group-level educational outreach intervention, designed to take account of identified barriers to change, can have a modest but sustained effect on prescribing levels. However, outreach is not always effective. The context in which change in prescribing practice is being sought, the views of prescribers concerning the value of the drug, or other unrecognised barriers to change may influence the effectiveness of outreach.

Cost-effectiveness and cost-utility of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine: randomised controlled trial.

BACKGROUND: The cost-effectiveness of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) has not been compared in a prospective study in primary care. AIMS: To determine the relative cost-effectiveness of TCAs, SSRIs and lofepramine in UK primary care. METHOD: An open-label, three-arm randomised trial with a preference arm. Practitioners referred 327 patients with incident depression. RESULTS: No significant differences were found in effectiveness or cost-effectiveness. The numbers of depression-free weeks over 12 months (on the Hospital Anxiety and Depression Scale) were 25.3 (95% CI 21.3-29.0) for TCAs, 28.3 (95% CI 24.3-32.2) for SSRIs and 24.6 (95% CI 20.6-28.9) for lofepramine. Mean health service costs per patient were pound 762 (95% CI 553-1059) for TCAs, pound 875 (95% CI 675-1355) for SSRIs and pound 867 (95% CI 634-1521) for lofepramine. Cost-effectiveness acceptability curves suggested SSRIs were most cost-effective (with a probability of up to 0.6). CONCLUSIONS: The findings support a policy of recommending SSRIs as first-choice antidepressants in primary care.

A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

OBJECTIVE: To determine the relative cost-effectiveness of three classes of antidepressants: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the modified TCA lofepramine, as first choice treatments for depression in primary care. DESIGN: Open, pragmatic, controlled trial with three randomised arms and one preference arm. Patients were followed up for 12 months. SETTING: UK primary care: 73 practices in urban and rural areas in England. PARTICIPANTS: Patients with a new episode of depressive illness according to GP diagnosis. INTERVENTIONS: Patients were randomised to receive a TCA (amitriptyline, dothiepin or imipramine), an SSRI (fluoxetine, sertraline or paroxetine) or lofepramine. Patients or GPs were able to choose an alternative treatment if preferred. MAIN OUTCOME MEASURES: At baseline the Clinical Interview Schedule, Revised (CIS-R PROQSY computerised version) was administered to establish symptom profiles. Outcome measures over the 12-month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression (HAD-D), CIS-R, EuroQol (EQ-5D) for quality of life, Short Form (SF-36) for generic health status, and patient and practice records of use of health and social services. The primary effectiveness outcome was the number of depression-free weeks (HAD-D less than 8, with interpolation of intervening values) and the primary cost outcome total direct NHS costs. Quality-adjusted life-years (QALYs) were used as the outcome measure in a secondary analysis. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were computed. Estimates were bootstrapped with 5000 replications. RESULTS: In total, 327 patients were randomised. Follow-up rates were 68% at 3 months and 52% at 1 year. Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients randomised to TCAs entered the preference arm than those allocated to the other choices. Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm. There were no significant differences between arms in mean cost per depression-free week. For values placed on an additional QALY of over 5000 pounds, treatment with SSRIs was likely to be the most cost-effective strategy. TCAs were the least likely to be cost-effective as first choice of antidepressant for most values of a depression-free week or QALY respectively, but these differences were relatively modest. CONCLUSIONS: When comparing the different treatment options, no significant differences were found in outcomes or costs within the sample, but when outcomes and costs were analysed together, the resulting cost-effectiveness acceptability curves suggested that SSRIs were likely to be the most cost-effective option, although the probability of this did not rise above 0.6. Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks. Further research is still needed on the management of depressive illness in primary care. This should address areas such as the optimum severity threshold at which medication should be used; the feasibility and effectiveness of adopting structured depression management programmes in the UK context; the importance of factors such as physical co-morbidity and recent life events in GPs' prescribing decisions; alternative ways of collecting data; and the factors that give rise to many patients being reluctant to accept medication and discontinue treatment early.

Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems.

In a randomized, placebo-controlled double-blind trial a combination of lofepramine, phenylalanine and vitamin B(12) was found to be effective in relieving the symptoms of multiple sclerosis (MS). The effect occurred within 2-4 weeks, and improved all types of symptoms in all types of MS. The combination was also effective in relieving symptoms in patients with chronic pain and chronic fatigue. We hypothesize that the action of this combined therapy may relate to activation of the noradrenergic locus coeruleus/lateral tegmentum (LC/LT) system which has the potential to influence the functioning of large areas of the brain and spinal cord.

A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder regime") in the treatment of multiple sclerosis.

OBJECTIVE: To determine whether combination therapy with lofepramine, L-phenylalanine, and intramuscular vitamin B-12 (the "Cari Loder regime") reduces disability in patients with multiple sclerosis. METHODS: A placebo controlled, double blind, randomised study carried out in five United Kingdom centres on outpatients with clinically definite multiple sclerosis, measurable disability on Guy's neurological disability scale (GNDS), no relapse in the preceding six months, and not on antidepressant drugs. Over 24 weeks all patients received vitamin B-12, 1 mg intramuscularly weekly, and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily, or matching placebo tablets. Outcome was assessed using the GNDS, the Kurtzke expanded disability status scale; the Beck depression inventory, the Chalder fatigue scale, and the Gulick MS specific symptom scale. RESULTS: 138 patients were entered, and two were lost from each group. There was no statistically significant difference between the groups at entry or at follow up. Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used. Both groups showed a reduction of 2 GNDS points within the first two weeks, and when data from all time points were considered, the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards. CONCLUSIONS: Patients with multiple sclerosis improved by 2 GNDS points after starting vitamin B-12 injections. The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit. More research is needed to confirm and explore the significance of this clinically small difference.

Fístula aortocava: complicación infrecuente tras rotura de aneurisma de aorta abdominal / Aortocaval fistula: an infrequent complication of aneurysm of the abdominal aorta

Se describe un caso de fístula aortocava (FAC) como complicación, muy infrecuente, de un aneurisma de aorta abdominal (AAA), debutando clínicamente con dolor en fosa lumbar derecha y fracaso renal. El diagnóstico se realizó por tomografía computarizada helicoidal (TCH) y fue confirmado por la cirugía. Los hallazgos por TCH consisten en un realce precoz de la vena cava inferior (VCI) de similar atenuación que la aorta abdominal (AA) en fase arterial y visualización de la comunicación entre la aorta y la vena cava inferior. (AU)

The effect of lofepramine and other related agents on the motility of Tetrahymena pyriformis.

Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression, they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn, normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium. The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50s for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocaine had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values.

Meta-analytical studies on new antidepressants.

A systematic search found 108 meta-analyses of the use of antidepressants in depressive disorders. Defining newer antidepressants as those introduced since the early 1980s, 18 meta-analyses were selected as being informative about their relative efficacy and tolerability in comparative randomised controlled studies (RCTs). Findings with higher confidence include: little difference in efficacy between most new and old antidepressants; superior efficacy of serotonin and noradrenaline re-uptake inhibitors (SNRIs) over selective serotonin re-uptake inhibitors (SSRIs); a slower onset of therapeutic action of fluoxetine over other SSRIs; a different side effect profile of SSRIs to TCAs with superior general tolerability of SSRIs over TCAs; poorer tolerability of fluvoxamine than other SSRIs in a within group comparison; no increased the risk of suicidal acts or ideation in fluoxetine compared with TCAs (or placebo) in low-risk patients. Findings with a lower level of confidence include: greater efficacy of TCAs than SSRIs in in-patients; greater efficacy of amitriptyline than SSRIs; better tolerability of moclobemide than TCAs; no demonstrable difference in tolerability between SSRIs and TCAs in the elderly; no better tolerability of fluvoxamine than TCAs; better tolerability of dothiepin (dosulepin) than SSRIs; better tolerability of sertraline and greater frequency of agitation on fluoxetine than other SSRIs in a within group comparison. In general, the meta-analyses were of uneven quality, as were the studies included, which limits the confidence in many of the results. Generalising from mostly short-term randomised controlled studies to clinical practice requires caution.

MRI changes in multiple sclerosis following treatment with lofepramine and L-phenylalanine.

As part of a large, randomized placebo-controlled trial of inpatients with multiple sclerosis (MS), a subsample of 15 underwent cerebral MRI at baseline and 6-months (eight on lofepramine and l-phenylalanine; seven on placebo). Unlike the placebo group, the active group showed a significant reduction in lesion number visible on T1-weighted scans (p < 0.05). The lateral ventricular volume increased, on average, by 1020 mm3 in the untreated group and 600 mm3 in the treated group. In the treated patients the ventricular size change correlated with both change in Gulick MS-related symptoms scale scores (rs = 0.71, p = 0.07) and Gulick MS-related activities of daily living scale scores (rs = -0.83, p = 0.02). It is concluded that treatment with lofepramine and l-phenylalanine is associated with significant MRI changes.

An investigation of the antidepressant properties of lofepramine and its desmethylated metabolites in the forced swim and olfactory bulbectomized rat models of depression.

The purpose of this study was to examine the metabolites of lofepramine (LOF), namely desipramine (DMI), desmethyl desipramine (DDMI) and desmethyl lofepramine (DML) in the forced swim and olfactory bulbectomized (OB) rat models of depression. In the first study, subacute treatment with DMI (10 mg/kg) and DML (20 mg/kg), but not LOF, reduced the immobility time in the forced swim test. In the "open field", chronic (14 day) treatment with all drugs attenuated the hyperactivity associated with olfactory bulbectomy. In the second experiment, a lower dose of DML (10 mg/kg) demonstrated activity following subacute treatment in the forced swim and following chronic treatment in the OB model. In addition, DDMI (10 mg/kg) was active in both models. From these results, it can be concluded that, at the doses employed, LOF and it's desmethylated metabolites, DMI, DML and DDMI, exhibits activity in the OB model. In contrast, lofepramine but not it's desmethylated derivatives is inactive in the forced swim test, perhaps suggesting the requirement of metabolic conversion of LOF to reveal antidepressant activity in this model.

[A case of allergic cross reaction between tricyclic antidepressants and maprotiline].

Although a 76-year-old woman with a diagnosis of depression began a course of maprotiline, the drug was discontinued after 14 days when she developed a rash. She was started on lofepramine in substitution for maprotiline. Four years later, lofepramine treatment was stopped and to amoxapine treatment introduced due to the aggravation of depressive symptoms. On the second day of this regimen, she developed a pruritic rash. She stopped the medication immediately. Because the rash disappeared gradually, lofepramine treatment was restarted. But her recovery was restrained and new skin lesions developed. Again, she stopped the medication, and the rash cleared within several days. This case suggests the existence of cross-allergenicity between tricyclic antidepressants and maprotiline.

Tricyclic antidepressants in adolescent depression. A case report.

A boy aged 11 years 11 months, with normal premorbid personality, presented with a severe depressive episode with somatic and psychotic features. A clinical response to amitriptyline was complicated by ECG changes leading to the abrupt withdrawal of amitriptyline, with the development of a withdrawal syndrome. Further trials of antidepressant medication were unsuccessful, including paroxetine (clinical deterioration), lofepramine (ECG changes and clinical deterioration), and trazodone (priapism). Finally, a good clinical response to dothiepin augmented with lithium was achieved. ECG changes were assessed as being idiosyncratic responses to medication, rather than ischaemic in nature. A dose/response relationship with dothiepin was observed. All medication was successfully stopped after 26 months of treatment. Clinical phenomena relevant to the development of guidelines for use of tricyclic antidepressants in childhood and adolescence are discussed.

A protocol for the pharmacologic treatment of major depression. A field test of a potential prototype.

BACKGROUND: Much attention is being given to developing clinical practice guidelines for management of mental health disorders. The aim of this study was to field test a prototype protocol for the pharmacologic treatment of Major Depression. METHOD: The protocol consisted of four, six week, treatment phases with critical choices in therapy defined by scores on the MADRS (Montgomery Asberg Depression Rating Scale). Observational data as collected on the behaviour of the protocol in terms of relevance, acceptability, ease of use and effectiveness. RESULTS: Effectiveness of the protocol was good for those patients who were retained within it, with three quarters of them attaining remission. However more than half of all patients dropped out-non attendance and adverse events being the most common reasons for this. CONCLUSION: The protocol for the treatment of Major Depression appeared relevant, easy to use and potentially effective. LIMITATION: Problems with non-adherence by both doctors and patients posed major challenges to the protocol's design. Such difficulties demonstrate the need to field test any proposed design as preconceptions about a protocol's performance may be misplaced. CLINICAL RELEVANCE: The protocol tested represents progress towards the goal of developing optimal strategies for the use of pharmacotherapeutic agents in the treatment of depression.

Treatment of major depression in general practice: a double-blind comparison of paroxetine and lofepramine.

A six-week, double-blind, randomised study was used to compare the efficacy, tolerability, safety and effect on cognitive function of paroxetine with that of lofepramine in the treatment of 138 patients with major depression in general practice. Efficacy was assessed using the Montgomery and Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) scale. Effect on cognitive function was assessed using the paired associate learning test and the serial "E' cancellation test. The results showed that the antidepressant efficacy of paroxetine was comparable to that of lofepramine in the treatment of depressed patients. Similar improvements in mean total MADRS scores were observed in both treatment groups, but a significantly greater improvement was seen in the CGI with paroxetine at weeks 2 and 4. The effect of treatment on cognitive function did not differ significantly across the two treatment groups, nor did the number of adverse events reported nor the overall tolerability.

The Galway Study of Panic Disorder. IV. Temporal stability of diagnosis by present state examination test-retest.

BACKGROUND: A long-term outcome study of DSM-III-R panic disorder included the Present State Examination (PSE) at baseline and follow up five to six years later. METHOD: PSE test-retest and individual within-patient change scores on various PSE syndromes were assessed for consistency with either a categorical view of panic disorder as a stable clinical entity or panic disorder as one facet only of a "general neurotic syndrome'. RESULTS: PSE profile at baseline was virtually identical with that at follow up. Few patients had changed in PSE syndrome diagnosis after five to six years. CONCLUSION: These data, although not conclusive, are supportive of the concept of DSM-III-R panic disorder as a stable clinical entity and are correspondingly difficult to reconcile with the view that panic disorder is but one facet only of a general neurotic syndrome.