Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients.

The efficacy and safety of fluvoxamine maleate, a selective serotonin reuptake inhibitor, was compared with placebo and imipramine in patients with major depressive disorder. Previous literature has cited a dose range of 100 to 300 mg/day of fluvoxamine maleate for the treatment of major depression; however, this study demonstrates that a dose range of 50 to 150 mg/day is as effective as imipramine (80-240 mg/day). After a 1- to 2-week, single-blind, placebo washout phase, 150 depressed outpatients were randomized to double-blind treatment with fluvoxamine maleate (50-150 mg/day), imipramine (80-240 mg/day), or placebo for 6 weeks. Fluvoxamine produced a significant therapeutic benefit over placebo (p < or = 0.05) as assessed by the total score on the Hamilton Rating Scale for Depression; imipramine (80-240 mg/day) produced similar results. The secondary outcome variables (i.e., Clinical Global Impression severity of illness item and 56-Item Hopkins Symptom Checklist depression factor) also showed significant differences between fluvoxamine maleate and placebo during three of the four final weeks of the study. Both fluvoxamine maleate and imipramine appeared to be safe and well tolerated by the majority of patients. As expected from the pharmacology of these agents, the imipramine groups reported more anticholinergic effects (dry mouth, dizziness, and urinary retention) and electrocardiographic effects, whereas the fluvoxamine group reported more nausea, somnolence, and abnormal ejaculation. The majority of these adverse events were mild to moderate and, with the exception of dry mouth (imipramine) and abnormal ejaculation (fluvoxamine), were transient. The data clearly demonstrate the antidepressant activity and tolerability of fluvoxamine maleate (50-150 mg/day) as compared with placebo; it is also as effective as the tricyclic antidepressant imipramine (80-240 mg/day) in patients with major depressive disorder.

Electrocardiographic findings during extended clinical trials of fluvoxamine in depression: one years experience.

INTRODUCTION: Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is used to treat depression. No significant effect on the electrocardiogram (ECG) has been reported during short-term controlled studies of SSRI's. We report a long-term (1 year) multi-center, double-blind controlled study of the ECG during treatment of depression with fluvoxamine (FX), active control medication (TCA), and placebo (PLA). METHOD: Initially ECGs were obtained from 1840 physically healthy, depressed outpatients who were treated with FX, TCA, or PLA for 6 weeks. A subset of these patients continued treatment for up to one year. Complete sets of ECGs were obtained from 462 of these patients. Patients whose depression was substantially improved in the initial 6-week study ("responder") received the same medication. Non-responders received a blinded active medication. Pre-treatment, intra-study, and past-treatment ECGs were recorded according to protocol. One blinded electrocardiographer measured and analyzed all ECG data. The effects of each medication upon the ECG were measured and compared. RESULTS: Of the 462 patients, 311 used FX, 100 used TCA and 51 used PLA. Analyses of ECG data for each treatment focused on changes in ECG measurements; % of normal ECGs, and % of individual ECG findings. The ECG changes during FX treatment were less than or not significantly different from the ECG changes with PLA treatment. The changes with TCA were as expected. CONCLUSIONS: Fluvoxamine treatment of depression for one year was not associated with any significant effect on the ECG.

SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems.

SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.

Modulation of the aversive qualities of shock through a central inhibitory cholinergic system in the rat.

Evidence has been supplied which suggests that a central inhibitory cholingeric (i.e., muscarinic) system may be involved in modulating the aversive qualities of electric shock in the rat. Central cholinergic stimulation via the administration of pilocarpine or arecoline the threshold for grid shock, while central acting anticholinergics (i.e., scopolamine and atropine) produced decrements in the threshold. Peripheral acting anticholinergics (e.g., methyl scopolamine, methyl atropine) were less potent than central acting drugs given in equivalent doses, while peripheral cholinergic stimulants (i.e., neostigmine, carbachol) were inactive. In addition, only the central acting stimulant pilocarpine, and not carbachol, was able to block the decrements noted in response to scopolamine hydrobromide administration. Finally, only arecoline, and not nicotine, was able to elevate the aversive threshold indicating that muscarinic receptor sites are probably involved in mediating the effects of central cholinergic stimulants.

The effects of metiamide on the "activity-stress" ulcer in rats.

Forty rats were housed in standard activity wheel cages and fed for only 1 hr per day. The animals were equally divided into 4 groups that received either saline, 12.5 mg/kg, 25.0 mg/kg or 50.0 mg/kg of metiamide, an H2 receptor antagonist, 3 times a day. All animals died within 11 days and all demonstrated significant gastric lesions in the glandular fundus of the stomach. The 50.0 mg/kg dosage group, however, demonstrated significantly fewer ulcers than the saline animals and the lesions that did occur were significantly smaller than those noted in the control animals. Several hypotheses were offered to explain these results which took into account metiamide's effects on gastric secretion and motor activity. It was suggested that secretion of acid may be an important contributing factor in the formation of gastric ulcers in animals subjected to the "activity-stress" procedure.

The effects of chronic morphine administration upon a modified Sidman avoidance schedule that utilizes response-independent shock.

Six male squirrel monkeys were subjected to a Sidman nondiscriminated avoidance schedule (R-S, S-S-20 sec) that superimposed 3-min conditioned stimuli (CS) unavoidable shock pairings upon the ongoing avoidance behavior. Five of the 6 animals demonstrated facilitated avoidance response rates during the CS, while one animal demonstrated suppressed rates during the CS. Morphine sulfate (0.5, 1.0, 2.0, 3.0, 4.0 mg/kg) altered these patterns, causing the suppressor to facilitate, while the facilitators demonstrated reduced levels of response elevation during the aversive CS. Morphine also led to a reliable reduction in overall response rate and an increase in the number of shocks received. No consistent drug effects were noted with regard to general motor activity. These results were interpreted to suggest that a potent analgesic agent, such as morphine, was able to reduce the level of fear motivation normally generated by the aversive CS. Since changes in relative rate during the aversive CS were quite reliable both within and between animals, it was suggested that this behavioral schedule might prove useful in assaying the fear-reducing qualities of a variety of drugs. A cautionary note, however, indicated that other explanations, most notably, a rate dependent hypothesis, could account for the data without assuming the level of fear was altered.