Cardiovascular effects of paroxetine

In a double-blind clinical study, electrocardiogram, blood pressure and systolic time intervals were measured in 40 depressive patients treated with either paroxetine (30 mg/day) or amitriptyline (150 mg/day) for 6 weeks. While amitriptyline significantly increased the heart rate, the QTc interval and the PEP/LVET ratio, paroxetine did not alter any of the cardiovascular parameters measured.     

The influence of psychotropic drugs on the ultrasonic calling of mouse pups

The influence of a range of commonly used psychotherapeutic drugs on the ultrasonic calling of mouse pups was assessed. The major tranquilizers chlorpromazine and haloperidol were without effect. Whereas tranylcypromine and imipramine were also inactive, amitriptyline suppressed the rate of calling. Some anxiolytic compounds such as meprobamate and amobarbital were without influence, although others such as diazepam, chloridazepoxide and ipsapirone decreased the number of calls. The influence of these drugs on body temperature was measured, as it is known to markedly influence the rate of ultrasonic calling. Although six out of ten drugs decreased body temperature, there was no evidence that this was related to the rate of ultrasonic calling. The possibility that the recording of ultrasonic calls could be used to screen for psychotropic activity is discussed.     

Blood noradrenaline and 5-HT levels in depressed women during amitriptyline or lithium treatment

Noradrenaline levels and platelet and free serotonin concentrations were studied in depressed women in-patients (n=78) before and during amitriptyline (n=41) or lithium treatment (n=37). Pronounced monthly differences in platelet serotonin level have been shown in these subjects before treatment. In all clinical subgroups (neurotic, involutional, manic-depressive patients) a significant fall in platelet serotonin level was observed with amitriptyline medication while an increase was noted with lithium. No significant correlations between serotonin concentrations and clinical outcome were found. Amitriptyline treatment also produced a decrease in peripheral noradrenaline concentration in all subgroups, while an increase was observed with lithium. Some correlations between noradrenaline level and degree of depression were noted in patients treated with amitriptyline or lithium. A more extended analysis of blood amine levels could supply meaningful information on the peripheral action of antidepressive drugs on noradrenaline and serotonin concentrations in depression.     

Brain concentrations of tricyclic antidepressants: Single-dose kinetics and relationship to plasma concentrations in chronically dosed rats

A previously reported method of measuring tricyclic antidepressant concentrations in brain tissue and plasma was used to measure amitriptyline (AMI) in rats following drug administration using different routes, doses, and time intervals. In rats given AMI intraperitoneally (IP), brain concentrations increased during the first 30 min after drug adminstration and then declined. Brain concentrations increased linearly with changes in IP dosage and increased logarithmically with changes in intravenous dosage. No simple relationship existed between brain and plasma concentrations in acutely dosed rats. However, a linear relationship existed between plasma and brain concentrations in chronically treated animals (r=0.96, P<0.001). The brain: plasma drug ratios observed in chronically treated rats corresponded to ratios reported in man. Thus, conclusions drawn from these studies can probably be extrapolated to the clinical situation. Based on our data, the molar concentration of drug achieved on therapeutic doses is 10^-5–10^-6 M. This information may aid in understanding the clinical relevance of in vitro drug: receptor binding studies which are typically reported in molar concentrations.     

Nonspecific factors and side effect complaints. Factors affecting the incidence of drowsiness in drug and placebo treated anxious and depressed outpatients.

Discriminant function analyses were applied to data obtained from anxious psychiatric outpatients treated with either chlordiazepoxide (n = 353) or placebo (n = 259) and depressed outpatients treated with either amitriptyline (n = 310) or placebo (n = 328), who had participated in controlled drug trials of 4 weeks' duration, in an attempt to identify factors associated with complaints of drowsiness made by these patients. Although the magnitude of the relationships between individual predictors and drowsiness was small, several factors emerged which had consistent impact across treatment groups. Predictors of complaints of drowsiness attributed to active drugs arose primarily from demographic attributes probably reflective of life style, and from illness and treatment history. In contrast, predictors of drowsiness attributed to placebo were almost exclusively confined to indices of the severity of several aspects of presenting symptomatology. In particular, more frequent complaints of drug-induced drowsiness were found among better educated individuals with an illness of long duration. Complaints of placebo-induced drowsiness were more common among patients with more severe emotional (phobic-obsessive) symptomatology and more frequent headaches and among those individuals in whom hypochondriasis was less severe.     

Interaction of Ro 4-1284 with doxepin, amitriptyline and desmethylimipramine on mouse avoidance behavior

Mouse avoidance performance was employed to study the interaction of Ro 4-1284 (2 and 8 mg/kg) with various dose levels of doxepin, amitriptyline and desmethylimipramine. Both prevention and reversal of Ro-induced blockade was examined. The antidepressants were capable of significantly antagonizing (prevention and reversal) the Ro-induced avoidance blockade. Amitriptyline and doxepin showed both antagonistic and potentiating actions to the Ro-effect on mouse avoidance — smaller doses tended to antagonize in the early phase; larger doses tended to potentiate in the later phase. Desmethylimipramine was antagonistic to Ro 4-1284 and only at toxic doses potentiated it. Prevention of the Ro-induced blockade, in general, was better demonstrated than its reversal by the antidepressant drugs. Doxepin showed interactions with Ro 4-1284 that were qualitatively similar to amitriptyline.     

Studies with activated charcoal in the treatment of drug overdosage using the pig as an animal model

Pigs were given large oral doses of paracetamol, amylobarbitone and amitriptyline. The effect of administering activated charcoal at varying intervals after dosing on the blood drug-level profiles of paracetamol and amylobarbitone was assessed by comparison with the profiles obtained when charcoal therapy was withheld. An appreciable effect on paracetamol absorption was demonstrated when charcoal was given up to l h after dosing. The amylobarbitone-dosed pigs exhibited delayed gastro-intestinal absorption of drug and this was substantially reduced by activated charcoal given 4 hrs after dosing. The pigs metabolised amitriptyline at too high a rate for meaningful studies to be undertaken with this drug.     

Announcements

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression based on our animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.     

A characteristic of the rate response which is common to several compounds that stimulate the heart.

Chronotropic effects of increasing concentrations of histamine, epinephrine, norepinephrine (when catecholamine uptake is blocked by amitriptyline), theophylline and caffeine were observed using isolated atrial pairs. Linear transformations of the dose-response curves for all the agents revealed similar straight line relationships. Inverse plots of the data of the chronotropic response to these compounds produces a series of linear curves analogous to similar plots of enzymatic activity. It has been well documented that all these agents have the common property of increasing cyclic AMP levels. Therefore, the present results lend support to the concept that cyclic AMP may play a critical role at some step in the regulation of the heart rate.