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.

Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission. The overall therapeutic efficacy of lofepramine is comparable to that of imipramine, amitriptyline, clomipramine, maprotiline and mianserin in patients with depression of varying severity, and coexisting anxiety. Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose. Thus, providing its apparent favourable side effect profile is confirmed in practice, lofepramine may be a valuable alternative for treatment of the depressed patient where a tricyclic is indicated.

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.

Behavioural and neuropharmacological properties of the dibenzazepines, desipramine and lofepramine: studies on the olfactory bulbectomized rat model of depression.

1. Lofepramine was compared with its major desipramine for its effects on adaptation to novel objects in the home cage (neophobia) and exploratory behaviours in both sham operated and olfactory bulbectomized rats. 2. In the test for neophobia (marble burying), the aversive response of bulbectomized rats differed from that of the sham operated animals, the bulbectomized rats showing a diminished aversive response. This response was unaffected by either antidepressant. 3. Of two tests for exploratory activity, the "open field" test clearly differentiated the bulbectomized rats treated with desipramine from those treated with lofepramine. In the lower doses used (1 and 10 mg/kg), only desipramine treatment significantly attenuated the hypermotility of the bulbectomized rats. In high doses (30 mg/kg), lofepramine also attenuated the hypermotility of the bulbectomized rats; this could have been due to the presence of high concentrations of the desipramine metabolite. In a non-stressful novel environment ('hole board'), neither drug significantly affected the behaviour of sham operated or olfactory bulbectomized rats. Neither antidepressant had noticeable anticholinergic properties as indicated by the number of faecal boli deposited. 4. Acute clonidine administration was found to attenuate the activity of rats in the 'open field' apparatus. This effect was attenuated following the chronic administration of desipramine but not lofepramine. It may be concluded that the pharmacological activity of lofepramine is independent of its metabolism to desipramine in vivo.

Effect of lofepramine on 5-HT function and sleep.

We studied the effect of the tricyclic antidepressant lofepramine (140-210 mg daily for 16 days) on 5-hydroxytryptamine 1A (5-HT1A) receptor sensitivity in healthy volunteers, using a buspirone neuroendocrine challenge paradigm (30 mg orally). We also studied the effect of lofepramine on platelet 5-HT content and sleep architecture. Lofepramine treatment did not alter the hypothermic, endocrine or amnesic effects of buspirone but significantly lowered platelet 5-HT content and decreased rapid eye movement sleep. Our findings suggest that at clinically used doses, lofepramine inhibits the uptake of 5-HT and produces changes in sleep architecture characteristic of tricyclic antidepressants. However, lofepramine does not appear to alter the sensitivity of 5-HT1A receptors.

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.

Chronobiology and its implications for pharmacotherapy of endogenous depression.

An open pilot study on 30 in-patients with endogenous depression showed a clear-cut circadian fluctuation of the therapeutical effect of single doses of lofepramine administered at three different times of the day (8 a.m., and 12 p.m.). A single-dose drug schedule with 210 mg lofepramine at 12 p.m. also proved superior (p less than .05) to the conventional divided-dose drug schedule with 70 mg lofepramine at three times of the day. The chronobiological background and the therapeutical consequences of these findings are discussed.

[Comparison of the effects of lofepramin and mianserin in depressed patients in a double blind trial]. / Wirkungsvergleich von Lofepramin und Mianserin an depressiven Patienten unter Doppelblind-Bedingungen.

The therapeutic efficacy of two newly developed anti-depressants lofepramine and mianserin was compared in a double-blind clinical trial in 30 depressed inpatients. During the treatment period of 4 weeks the depressive symptoms assessed by the Hamilton Rating Scale for Depression decreased in both groups. In this trial a stronger influence of lofepramine on the factor 'retarded depression' could be demonstrated (p = 0.08). In addition lofepramine showed a significantly better reduction of anxious reactions than mianserin (p less than 0.01). Concerning tolerance, no difference between the two drugs was observed.

The comparative antidepressant value of lofepramine and amitriptyline. Results of a controlled trial with comments on the scales used.

A double-blind controlled trial comparing the antidepressant activity of amitriptyline with lofepramine is reported. Forty-six patients entered the 4-week trial. Analysis of the Hamilton Depression Rating Scale scores at the beginning and end of the trial showed no significant difference between the therapeutic efficacy of lofepramine and amitriptyline. However, patients with endogenous depression responded significantly more rapidly to lofepramine as measured by Visual Analogue Scales and showed a significantly greater degree of clinical improvement after 4 weeks' treatment, as measured by Global Assessment. Adverse effects were similar in the two treatment groups. The use of rating scales in trials of depressive illnesses is discussed. The Visual Analogue Scale for depression was found to be a simple, useful and valid measure.

3H-imipramine binding to previously frozen platelet membranes from depressed patients, before and after treatment.

3H-imipramine binding in 39 drug-free patients with major depression and 44 healthy controls did not differ significantly between the two groups, in male or female subjects or in subgroups of depressed patients divided by endogenicity or dexamethasone suppression test result. 3H-imipramine binding in depressed patients drug-free for less than three weeks did not differ from those drug-free for longer intervals or from controls. A significant seasonal variation of 3H-imipramine Bmax was found, with lower values in summer and autumn. Treatment of depressed patients with imipramine or lofepramine for six weeks increased KD and Bmax. Methodological modification (in preparation and storage of platelets) does not explain the major differences in results between this study (using frozen platelets), a previous one (using freshly prepared platelets) and others in general, although it might contribute to the range of values reported.

Capgras syndrome in association with lithium toxicity.

Capgras syndrome in association with lithium toxicity is described in a 74-year-old woman. Lithium toxicity should be considered when new delusions occur during lithium therapy.

Simultaneous determination of lofepramine and desipramine by a high-performance liquid chromatographic method used for therapeutic drug monitoring.

A simple reversed-phase HPLC method with ultraviolet detection for the simultaneous measurement of lofepramine and desipramine is described. Only a single alkaline extraction was used, with clomipramine as internal standard. The column used was a Supelco PCN column, and the mobile phase was acetonitrile-methanol-0.015 M phosphate buffer (120:35:100, v/v). The average recoveries were 78.8% for desipramine and 103.8% for lofepramine, and limits of quantitation were 25 and 5 nmol/l, respectively. The inter-assay C.V.s for lofepramine and desipramine were 6.0 and 7.6%, respectively. The method is specific and has excellent accuracy, and has been used for therapeutic drug monitoring of patients with depressions treated with lofepramine. Mean steady-state plasma concentrations found for lofepramine and desipramine were 8.5 +/- 6.1 and 123.6 +/- 120.6 nmol/l, respectively. It is concluded that lofepramine in itself has an antidepressive effect.

Worsening of pica as a symptom of depressive illness in a person with severe mental handicap.

The case of a person with severe mental handicap whose pica became uncontrollable during episodes of depressive illness is described. Treatment of the depression with lofepramine markedly reduced the pica, and withdrawal of lofepramine led to recurrence. It is suggested that biological symptoms of depression should be monitored in people with severe mental handicap who show significant episodic worsening of long-standing repetitive behaviour.

Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine.

BACKGROUND: This study was designed to establish whether (as suggested in a number of open and relatively small controlled trials) lithium augmentation is more effective than continued antidepressant alone, where response to a standard course of antidepressant treatment has been absent or partial. METHOD: Lithium or placebo was added on a double-blind basis for six weeks to the drug regime of 62 patients with major depressive illness (in both hospital and primary care settings) who had failed to respond to a controlled trial of fluoxetine or lofepramine. Response was defined as a final Hamilton Depression Rating Scale (HDRS) score of < 10. RESULTS: Response was seen more frequently in patients taking lithium (15/29) than in those remaining on antidepressant alone (8/32; P < 0.05). Rapid response to lithium augmentation (LA) was not consistently observed in this cohort. Mean HDRS scores after six weeks were significantly lower (P < 0.01) in the lithium group after excluding those who had not achieved significant exposure to lithium (arbitrarily defined as two or more lithium levels > or = 0.4 mmol/l). No differences in the efficacy of LA were apparent between fluoxetine and lofepramine. CONCLUSIONS: Our results confirm that LA is a useful strategy in the treatment of antidepressant-resistant depression. Partial response was, however, frequently observed with continued antidepressant treatment alone, and the superiority of LA appears to depend on achieving adequate serum lithium levels.