Fluvoxamine and tricyclic antidepressants (TCAs): how do the TCAs compare as "new" drugs with established fluvoxamine?

The tricyclic antidepressants (TCAs) are still considered as first-line treatment for depression, despite the availability of the selective serotonin reuptake inhibitors (SSRIs). This paper considers the current situation in reverse by assuming that only the SSRIs, in particular fluvoxamine, are available and the TCAs (amitriptyline, imipramine, clomipramine and dothiepin) are the potential "new" drugs. The criteria for an "ideal" antidepressant are discussed and the efficacy, safety and cost-effectiveness of these agents are compared.

Fluvoxamine versus clomipramine in the treatment of obsessive compulsive disorder: a multicenter, randomized, double-blind, parallel group comparison.

BACKGROUND: To examine the efficacy of fluvoxamine and clomipramine in obsessive compulsive disorder and to compare their tolerabilities. METHOD: In this multicenter, randomized, double-blind trial, fluvoxamine (100-250 mg/day) was compared with clomipramine (100-250 mg/day) for 10 weeks in the treatment of 66 psychiatric outpatients, aged 18 to 65 years, with a diagnosis of obsessive compulsive disorder. The main efficacy variable was the Yale-Brown Obsessive Compulsive Scale; secondary variables were the National Institute of Mental Health Global Obsessive Compulsive Scale and the Clinical Global Impressions-Improvement scale. RESULTS: Seventeen patients withdrew prematurely, 6 in the fluvoxamine group and 11 in the clomipramine group. In the intent-to-treat population (34 fluvoxamine patients and 30 clomipramine patients), there were no significant differences with respect to the mean reduction in total Yale-Brown Obsessive Compulsive Scale score (last observation carried forward) at any time-point; a mean reduction of 8.6 (33%) was seen in the fluvoxamine group and 7.8 (31%) in the clomipramine group. Similar results were obtained in virtually all secondary variables. The only exception was the obsession-free interval for the Yale-Brown Obsessive Compulsive Scale, which was significantly longer in the fluvoxamine group, especially in a population of patients with disease of > 12 months' duration (F = 5.298, df = 1, p = .026). Adverse events were mostly tolerable; 9 patients (5 receiving fluvoxamine, 4 receiving clomipramine) withdrew due to adverse events related to treatment. CONCLUSION: Fluvoxamine and clomipramine were equally effective in the treatment of obsessive compulsive disorder. Both agents were well tolerated; fluvoxamine produced fewer anticholinergic side effects and caused less sexual dysfunction than clomipramine, but more reports of headache and insomnia.

Fluvoxamine in the treatment of depressive illness. A series of double-blind hospital based comparative studies carried out in the UK.

A series of double-blind hospital based studies comparing fluvoxamine with other antidepressants in depressed patients is reviewed. Overall there were no significant differences in terms of efficacy between fluvoxamine and the comparators (amitriptyline, dothiepin, lofepramine and mianserin). Fluvoxamine was shown to be associated with a low incidence of anticholinergic, cardiovascular or sedative effects. This profile of activity, together with low toxicity in overdosage, has established the place of fluvoxamine in the treatment of depressive illness.

A double-blind, randomised comparison of fluvoxamine with dothiepin in the treatment of depression in elderly patients.

The efficacy and tolerability of the selective 5-HT reuptake inhibitor fluvoxamine were compared with the tricyclic dothiepin in 52 elderly (age greater than 64 years) hospital patients in a multi-centre double-blind randomised trial. Patients met DSM-III criteria for 'major depressive episode' and scored greater than 29 on the Montgomery Asberg Depression Rating Scale (MADRS) after a one-week placebo baseline. Active treatment was for six weeks. The dosage of both drugs was 50 mg nocte for three days, 100 mg nocte for the remainder of the first week, thereafter increasing to a maximum of 200 mg/day according to response/tolerance. MADRS scores improved by 63.5% with fluvoxamine and 60.0% with dothiepin; there were no significant differences between treatments at any assessment. Nausea, dizziness, headache, somnolence and constipation in both groups, plus dry mouth and asthenia in the dothiepin group were more frequent than single reports. Two patients in each group discontinued treatment owing to unwanted effects. There were no clinically significant changes in haematological, biochemical or cardiovascular parameters.

A multicentre double-blind comparative trial of fluvoxamine versus lorazepam in mixed anxiety and depression treated in general practice.

Fluvoxamine, a selective serotonin reuptake inhibitor, was compared with lorazepam in a multicentre double-blind, parallel group study in 112 general practice patients with mixed anxiety and depression. For inclusion, patients were required to have minimum baseline scores of 21 on the Montgomery-Asberg Depression Rating Scale (MADRS) and 11 on the Clinical Anxiety Scale (CAS). Treatment was for 6 weeks. There were no significant differences between treatments at any point except in an elderly subgroup in whom anxiety improved more rapidly with lorazepam. There were significant improvements in MADRS, CAS and global ratings compared with baseline at all subsequent assessments. Improvement continued during the whole treatment period. Lorazepam produced more sedation, whilst fluvoxamine produced significantly more nausea and vomiting; this was usually early in onset and, if tolerated, resolved during the course of the study. As it is now widely recognized that benzodiazepines should only be given in short courses of 2-4 weeks, the continued improvement up to 6 weeks has implications regarding choice of treatment.

A double-blind, randomized comparison of fluvoxamine with mianserin in depressive illness.

The efficacy and CNS effects of the selective 5-HT re-uptake inhibitor fluvoxamine were compared with mianserin in depressed hospital out-patients in a double-blind randomized trial. Patients had to meet DSM-III criteria for Major Depressive Episode and achieve a score of at least 30 on the Montgomery-Asberg Depression Rating Scale (MADRS) after a 1-week placebo baseline period. Active treatment was for 6 weeks with an initial dose of either 100 mg fluvoxamine or 60 mg mianserin; after 1 week the dosage could be increased to 300 mg or 180 mg, respectively. Data from 63 patients (30 received fluvoxamine) were analyzed. The treatment groups were comparable with regard to age and history and severity of depression. Efficacy assessments showed similar improvements with each drug; MADRS scores improved by 65.6% with fluvoxamine and by 60.8% with mianserin. There were no significant differences between treatments at any assessment. Sedative effects were assessed using the Leeds Sleep Evaluation Questionnaire and the Digit Symbol Substitution Test. Mianserin caused a shift towards sedation in the first week in all visual analogue scales; getting to sleep and sleep quality were improved but waking was more difficult than with fluvoxamine. Similarly, the mianserin group performed less well on the Digit Symbol Substitution Test. The study confirmed that both drugs are effective treatments for depressive illness but that mianserin gives rise to sedation during the first week.

Affective disorders in general practice. Treatment of 6000 patients with fluvoxamine.

A total of 6258 patients seen in general practice complaining of low mood with or without associated somatic symptoms was studied. The mean patient entry score on the Montgomery-Asberg Depression Rating Scale (MADRS) was 29.69 (moderately severe depressive disorder). Three-quarters (73%) of the patients were female, average age was 46.1 years, and a reactive element was considered to be present in 43%. Patients received fluvoxamine, a novel anti-depressant, over a treatment period of 6 weeks, dosage starting at either 50 or 100 mg at night increasing after the first week, if necessary, to a maximum of 300 mg per day. Results were analyzed for 5625 patients. Efficacy of treatment was assessed using the MADRS, Psychosomatic Symptom Scale and Clinical Global Impression scales. During treatment, there was a marked improvement in mood and a parallel improvement in somatic symptoms; there was no difference in overall response between those with or without somatic symptoms. By Week 6, patients had improved by approximately 65%, with suicidal ideation being most marked at 81%. Patient compliance was good, the most commonly reported unwanted effect being nausea. In overdoses up to 2 g fluvoxamine no lasting toxic effects were observed. In an 'elderly' sub-group of 1096 patients aged 60 years and over, efficacy and the incidence of unwanted effects were similar, but the drop-out rate due to intolerance was greater than in the younger age sub-group.

Some studies of the action of betahistine at H1 and H2 receptors for histamine.

Betahistine produced a concentration-dependent contraction of the guinea-pig ileum and was about 27 times less active than histamine in this respect. Betahistine induced desensitization of contractile responses to histamine in the guinea-pig ileum. The H1 histamine receptor antagonist mepyramine was a competitive antagonist of the action of betahistine on the guinea-pig ileum. Betahistine caused relaxation of the rat uterus contracted by acetylcholine, and this action of betahistine was blocked by the H2 receptor antagonist cimetidine. Betahistine had a concentration-dependent positive chronotropic action on isolated guinea-pig atria, and in this respect was tenfold less potent than histamine. The action of betahistine on the atria was blocked by the H2 receptor antagonist YM11170. Betahistine caused a concentration-related contraction of the isolated lung parenchymal strip of the guinea-pig, and YM11170 potentiated this effect. Betahistine failed to release histamine from rat peritoneal mast cells at concentrations up to 100 microM and it did not prevent histamine release induced by either substance P or anti-IgE. Betahistine produced a dose-related flare and wheal reaction when injected intradermally into human skin. It is concluded that betahistine has agonist activity at both H1 and H2 receptors for histamine.

An evaluation of the bile acid binding and antacid properties of hydrotalcite in hiatus hernia and peptic ulceration.

The bile acid binding and antacid properties of hydrotalcite were studied in 25 patients with hiatus hernia or peptic ulceration. Hydrotalcite was found to have significant bile acid binding properties in the presence of free acid in the stomach. There was a definite antacid effect in both pathological entities. These results suggest that hydrotalcite may be an effective therapeutic agent in upper gastro-intestinal ulceration, warranting further investigation in lesions which are thought to involve both hydrochloric acid and bile acids in their pathogenesis.