A new class of antiarrhythmic--defibrillatory compounds.

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in humans. Currently used antiarrhythmic drugs are aimed at preventing initiation of VF by decreasing the incidence of arrhythmias which can lead to VF. This approach today seems to be insufficient. On the basis of reports that VF can terminate spontaneously in various mammals, and even in humans, we propose pharmaceutical enhancement of self-ventricular defibrillation as a new therapeutical approach. Data obtained over the last decade indicate that a high cardiac extraneuronal noepinephrine level during VF facilitates self-defibrillation. Dibenzazepines (tricyclic antidepressants) and phenothiazines elevate norepinephrine level by inhibiting norepinephrine reuptake and were found to exhibit defibrillatory activity. The relationship of chemical structure to defibrillatory activity was studied in a group of dibenzazepine and phenothiazine compounds.

Ventricular defibrillating properties of catecholamine uptake inhibitors.

Ventricular fibrillation (VF) is a fatal event in humans unless electrical defibrillation is applied within minutes. Recent publications describe spontaneous termination of VF in various animals and even in humans. Certain drugs can transfer a fatal, sustained VF (SVF) into a self-terminating, transient VF (TVF). Based on results obtained in animals of various species and ages, we have suggested that the occurrence of TVF requires a high cardiac catecholamine level at the time of VF. According to our hypothesis, drugs which decrease catecholamine reuptake by the sympathetic nerve terminals will increase the ability of the heart ventricles to defibrillate spontaneously. In the present study, we examined the effects of desipramine, maprotiline, mianserin, iprindole, cocaine and amphetamine on the type of VF in cats exhibiting SVF prior to the treatment. The results show that the ability of these compounds to transfer SVF to TVF is closely related to their potency to inhibit catecholamine reuptake. The establishment of the catecholamine related mechanisms of TVF may lead to the development of a new class of antiarrhythmic-defibrillatory drugs.

Effects of antidepressant drugs on the behavior of olfactory bulbectomized and sham-operated rats.

Removal of the main olfactory bulbs in rats has been shown to alter neuronal function in brain areas involved in emotional regulation and homeostasis. These neuronal alterations result in maladaptive behavioral patterns and elevated plasma corticosterone that are suggestive of the symptom profile of patients with primary unipolar depression. Moreover, the endocrine and behavioral deficits of bulbectomized rats are reversed by the chronic administration of drugs that reverse the symptoms of depression in people when given chronically. However, the therapeutic improvements seen in patients with depression are not directly due to molecules of the antidepressant drug but rather to some relatively long-lasting compensatory change induced in the neuronal substrate by the drug. The present research demonstrates that the reversal of the olfactory bulb lesion deficits following chronic antidepressant drug administration in rats is not due to molecules of the drug per se but rather to some drug-induced change in the neuronal substrate that continues for at least 5 days after the last dose of drug. These endocrine, behavioral, and pharmacological similarities suggest that the study of rats with olfactory bulb ablation may make significant contributions to the understanding of the neuroscience of primary unipolar depression in humans.

Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study.

The authors administered lithium carbonate, 900 mg/day, in an open study to seven patients with a major unipolar depression refractory to 3-week treatment with iprindole, 90 mg/day, a tricyclic antidepressant devoid of any action on monoaminergic reuptake. All patients showed clinically significant improvement within 48 hours. Since iprindole induces in the animal a sensitization of forebrain neurons to serotonin (5-HT), as do other tricyclic antidepressants, and lithium enhances the activity of 5-HT neurons, the authors propose that an enhanced release of 5-HT on sensitized target neurons might underlie the rapid antidepressant effect in tricyclic-refractory depression when lithium is added to the treatment regimen.

Noradrenergic function and depression, too much or too little?

Antithetical hypotheses as to CNS noradrenergic function in depressed patients can be constructed from results of pharmacological studies of the effects of antidepressant drugs. The experimental data supporting each of these opposing propositions is briefly reviewed in this paper. Finally, the results of clinical studies of noradrenergic function in depressed patients are noted and discussed in terms of these disparate hypotheses.

Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.