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In 47 patients ECG tracings were recorded and cardiovascular values determined before therapy, during treatment with antidepressive agents after it had been in progress for at least 3 weeks, and 4 weeks after withdrawal of therapy. In a further 19 patients in whom antidepressive therapy could not be withdrawn, the same test battery was repeated after an average period of 13 months. No serious disturbances of cardiac rhythm were detected and certain changes in ECG criteria (prolongation of PR interval, widening of QRS complex, prolongation of QTc time and T-wave flattening) proved to be reversible. There was no difference between tricyclic and tetracyclic antidepressive agents. We are nevertheless of the opinion that ECG and cardiac function should be carefully monitored in elderly patients and in those on prolonged therapy with high doses of antidepressives. The results of this study are discussed and compared with previously published findings.
1. In man, the antidepressant agent 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone) on oral dosing was mainly eliminated in urine (80% dose in 12 h). 2. Plasma concn. of total radioactivity was max (5.8 micrograms equiv./ml) at 30 min to 1 h after administration and declined rapidly (t1/2, 1.25 h). Unchanged drug accounted for 48, 32 and 13% of plasma radioactivity at 15 min, 1 h and 6 h, respectively. 3. The drug was extensively metabolized. The major urinary metabolites were 3-(3-carboxyphenyl)-5-hydroxymethyl-2-oxazolidinone and a glucuronide of toloxatone. A minor urinary metabolite, characterized as a phenolic derivative, was also excreted conjugated.
The effect of seventeen established or possible antidepressant agents on the synthesis of 5-HT, noradrenaline and dopamine in rat brain has been investigated by measuring the accumulation of 5-hydroxytryptophan and DOPA induced by an inhibitor of the aromatic L-aminoacid decarboxylase (3-hydroxybenzylhydrazine hydrochloride, 100 mg/kg i.p.). All the established inhibitors of 5-HT, noradrenaline and dopamine uptake were found to inhibit the synthesis of the respective monoamines, presumably by influencing a receptor-mediated feedback mechanism. A close correlation appears to exist between blockade of transmitter uptake and inhibition of transmitter synthesis. The results support current ideas on the mode of action of antidepressant agents.
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The author distinguishes inhibition as a symptom from inhibition as a processus in the three following situations: a) Antidepressants and melancholic inhibition: the action on inhibition is studied referring to Kielholz classification of antidepressants. The author points out the risk of suicide by suppressing inhibition. b) Antidepressants and chronical psychoses: the author compares effects of antidepressants and stimulating neuroleptics in these syndroms. He thinks that with the two types of psychotropic drugs, one can obtain a desinhibitory effect. But antidepressants can be better used in paranoid personnalities, loss of ego boundaries, and some schizophrenic-like syndroms, when neuroleptics seem to be more desinhibitory in hebephrenics. The author stresses the depressive core in these psychotic personnalities. c) The antidepressant effect has been studied in neurotic depressions. The author describes essentially cases with reinforcement of inhibition as a negative therapeutic reaction by antidepressants. It deals with neurotic depressions evoluting on narcissic personnality back ground.
Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.
3,3-Diphenylcyclobutylamine (4), N-methyl-3,3-diphenylcyclobutylamine (6), and N,N-dimethyl-3,3-diphenyl-cyclobutylamine (7) have been prepared and tested as potential antidepressant agents. The secondary (6) and tertiary (7) amines strongly decrease the accumulation of NA and 5-HT in brain slices in vitro and in vivo. The cyclobutylamines also cause motor stimulation. The most potent compound in this respect is the tertiary amine 7. The increase in locomotion is not blocked by pretreatment with phenoxybenzamine, methergoline, or alpha-methyltyrosine. Pretreatment with pimozide or reserpine reduces the hyperactivity induced by 7. This hyperstimulation seems to be caused by a mechanism of action which differs from that of amphetamine. 7 may cause increase in locomotion by release of dopamine from granular stores.
The EEG and MUA (multiple unit activity) of mesencephalic reticular formation (MRF), area hypothalami posterior (PH), and area hypothalami anterior (AH) were studied in chronically implanted freely moving cats. The effects of thyrotropin-releasing hormone (TRH) and some antidepressant agents were tested on neuronal activity. Desipramine and imipramine resulted in a dose-dependent decline of MUA of all structures with the most significant decrease of activity in PH. A single injection of TRH resulted in slight or moderate gross behavioral changes and vegetative excitation lasting for 30-50 min with variable MUA levels. In the course of repetitive TRH treatment on consecutive days the gross behavioral changes and the vegetative symptoms failed to develop by the 3rd or 4th day. By that time the MUA changes of PH and MRF showed similar characteristics in response to TRH administration which was observed following the injection of desipramine and imipramine. The drugs, except for TRH, induced a suppression of paradoxical sleep cycles.
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