Pulse Intravenous Clomipramine as an alternative antidepressant treatment to ECT. A pilot study

Background and Objectives: The aim of the study was to examine the antidepressant effect of a single pulse dose of intravenous clomipramine (200 mg i.v.) followed by oral administration as an alternative method to electroconvulsive therapy. Methods: Twenty-one inpatients (8 male, 13 female) with major depression were included. Depression severity was measured by Montgomery Asberg Rating Scale (MADRS) and Clinical Global Impression severity scale (CGI-S) before the pulse dose and 1 week after. The day after the pulse dose, the patient was medicated with 75 mg of oral clomipramine and from day two with 150 mg clomipramine daily. Results: The MADRS score dropped with 39% ± 22% and the CGI score with 28% ± 19% in one week. The improvement of the MADRS score after one week was 13.1 (C.I.9.5-17.0). CGI-ratings dropped from a mean of 5.5 (SD 1.2) to 3.9 (SD 1.1), an improvement of 28% ± 19%.(C.I. 1.0-2.1). Both improvements were significant (p<000.1). Conclusions: Single pulse dose clomipramine administration ameliorates depressive symptoms, and may be an alternative to ECT. Received 27 December 2006 Revised 29 June 2007 Accepted 24 July 2007 Background and Objectives Since the introduction of tricyclics and subsequently followed by the selective serotonin reuptake inhibitors (SSRIs) and lately SNRIs as antidepressants, delayed onset of action and lack of response have been significant clinical problems in the treatment of depression. The cause of delayed onset of therapeutic response is not known, but a hypothesis is that the pharmacokinetic characteristics of these medications may play a role1. ECT is often a treatment of choice in treatment refractory depressions, but its role is limited by several factors as patient acceptance, high costs and, in some countries, legal restrictions. ECT given three times weekly takes between two and five weeks, often requiring in-patient care in a hospital. There is a need for alternative treatments, which preferably have a quick onset of action, high response rate and low costs. Chiodo et al.2, extrapolating from animal experiments, suggested that a single treatment with an antidepressant could be as effective as repetitive treatments. Pulse loading versus gradual dosing of intravenous clomipramine in outpatients with obsessive-compulsive disorder has been tested. A significantly greater improvement was achieved for the pulse loading group compared to the gradual dosing group by the end of week 13. The main pharmacodynamical effect of clomipramine is to inhibit neuronal re-uptake of noradrenaline and serotonin in the synaptic cleft. Clomipramine undergoes first-pass metabolism with production of the active metabolite desmethylclomipramine, which is a selective noradrenergic re-uptake inhibitor. With gradually increasing dosing of clomipramine the plasma concentrations of desmethylclomipramine (noradrenergic action) is 40-85% higher than the concentration of clomipramine at a dose level of 75 mg/day4. By pulse dose administration the first pass metabolism is avoided and a high level of clomipramine, which is both serotonergic and noradrenergic active (dual action), is rapidly achieved, which could lead to a more rapid and robust antidepressant effect5. In 1989, Pollock et al.6 performed a double-blind, randomized trial of oral vs. intravenous clomipramine hydrochloride pulse-loading dosing regimens on 22 inpatients with a diagnosis of major depressive disorder (score on 21-item Hamilton Depression Rating scale, ≥ 18)7. Patients were given either an evening infusion of 150 mg of clomipramine hydrochloride and placebo tablets or 150 mg of oral clomipramine hydrochloride and an isotonic saline infusion. Twenty-four hours later, this procedure was repeated using a dose of 200 mg clomipramine hydrochloride. No medication over the next five days was then given. The mean Hamilton Depression Rating Scale score for all patients, five days after pulse loading, had dropped by 35%. This improvement was significant. There were no significant differences in either efficacy or side effects between the two groups. Another double blind, placebo-controlled trial on sixteen nonsuicidal adolescents with major depressive disorder was designed by Sallee et al.8. In this study, a single dose of clomipramine (200 mg i.v., n = 8) was compared with saline placebo (n = 8). The adolescents who received pulse clomipramine treatment demonstrated significant decreases in Hamilton Depression Rating Scale scores from baseline at 6 days but not at 36 hours. There was a significant difference from the effect of placebo. The intravenous pulse clomipramine was well tolerated. 264 MAJ-LIZ PERSSON ET AL.