Lofepramine

Cost-effectiveness and cost-utility of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine: randomised controlled trial.[Pubmed:16582060]

Br J Psychiatry. 2006 Apr;188:337-45.

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.

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.[Pubmed:12376086]

Med Hypotheses. 2002 Nov;59(5):594-602.

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 controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.[Pubmed:15876362]

Health Technol Assess. 2005 May;9(16):1-134, iii.

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.

A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder regime") in the treatment of multiple sclerosis.[Pubmed:12185153]

J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):246-9.

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.

An investigation of the antidepressant properties of lofepramine and its desmethylated metabolites in the forced swim and olfactory bulbectomized rat models of depression.[Pubmed:10082234]

Eur Neuropsychopharmacol. 1999 Jan;9(1-2):101-5.

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.

The effects of lofepramine and desmethylimipramine on tryptophan metabolism and disposition in the rat.[Pubmed:1867646]

Biochem Pharmacol. 1991 Jul 25;42(4):921-9.

Acute and chronic administration of Lofepramine and its major metabolite desmethylimipramine (DMI) to rats elevates brain tryptophan concentration, thereby enhancing cerebral 5-hydroxytryptamine (5-HT) synthesis, by increasing the availability of circulating tryptophan to the brain, secondarily to inhibition of liver tryptophan pyrrolase (tryptophan 2,3-dioxygenase, L-tryptophan:O2 oxidoreductase, decyclizing; EC 1.13.11.11) activity. The pyrrolase inhibition by Lofepramine occurs independently of metabolism to DMI, because it can be demonstrated directly in vitro. Lofepramine also differs from DMI in its action profile on the above and related aspects of tryptophan metabolism and disposition. These results demonstrate that Lofepramine influences tryptophan and 5-HT metabolism and disposition independently of its major metabolite DMI, and are discussed briefly in relation to the mechanism of action of antidepressants.

A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review.[Pubmed:2891742]

Int Clin Psychopharmacol. 1987 Oct;2(4):281-97.

The effects of the novel tricyclic antidepressant Lofepramine were compared with that of its principal metabolite desipramine. In double-bind clinical trials, Lofepramine has been shown to be as effective as desipramine and other comparator tricyclic antidepressants in the treatment of endogenous and reactive depression, but there are some differences between them. Thus the acute toxicity of Lofepramine is approximately one-fifth that of its metabolite; Lofepramine is a less potent muscarinic receptor antagonist than desipramine (verified by clinical studies in volunteers and depressed patients); Lofepramine is less likely to produce conduction defects than desipramine. Neurochemical studies show that both Lofepramine and its metabolite are potent noradrenaline uptake inhibitors in vitro and evidence is presented to suggest that Lofepramine may release this amine following chronic administration in vivo; both drugs slightly increase serotonin turnover under these conditions and down-regulate cortical beta-adrenoceptor function. Unlike desipramine and most clinically effective antidepressants, Lofepramine was inactive in attenuating the hyperactivity of olfactory bulbectomized rats in the "open field" apparatus, and in reversing acute clonidine induced hypomotility. From such tests it appears unlikely that the active metabolite, desipramine, is formed in the brain in sufficient concentrations after chronic Lofepramine administration to make a substantial contribution towards the pharmacological activity of the parent compound.

Lofepramine (Lopramine) is a potent tricyclic antidepressant and is extensively metabolised to Desipramine. The antidepressant activity of Lofepramine stems from the facilitation of noradrenergic neurotransmission by uptake inhibition. Lofepramine may also potentiate serotoninergic neurotransmission by inhibition of the neuronal uptake of serotonin and the enzyme tryptophan pyrrolase. Lofepramine has significant anxiolytic efficacy in addition to its antidepressant properties.

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