Trazodone in late life depressive states: a double-blind multicenter study versus amitriptyline and mianserin

Seventy five elderly depressed in-patients, ages ranging from 60 to 83 years, diagnosed as Major Depression according to DSM III were treated, under double-blind conditions, with 75 mg Amitriptyline (AMI) (26 patients), 60 mg Mianserin (MIA) (24 patients) or 150 mg Trazodone (TRZ) (25 patients) p.o. for 5 weeks. There were no differences in the clinical outcome between the three groups of patients at the end of the trial, with a significant amelioration (P<0.01) at the Hamilton Rating Scale for Depression and Geriatric Depression Scale. TRZ showed a significantly lower incidence of side effects compared to MIA and AMI. Atypical antidepressants, including TRZ, seem more suitable for treating elderly depression than the first generation antidepressants on the basis of risk/benefit ratio considerations.     

Measurement of plasma levels of tricyclic psychoactive drugs and their metabolites by UV reflectance photometry of thin layer chromatograms

Summary A method has been developed for the determination of perazine, clozapine, imipramine and amitriptyline and their demethylated metabolites in plasma. Other metabolites measured were perazine sulfoxide and the N-oxides of clozapine and perazine, the latter two following their reduction to the parent drugs with ascorbic acid. 10-Hydroxynortriptyline was identified as an amitriptyline metabolite in plasma. The general procedure included extraction of alkalinized plasma samples (3 – 6 g) with benzene or toluene and thin layer chromatography of the extracts, followed by reflectance photometry of the plates at appropriate wave lengths in ultraviolet light. Spots of questionable identity were further characterized by two-dimensional chromatography and by colour reactions. The recoveries of compounds added in therapeutic concentrations were between 70 and 98 %. The limits of detectability were 5 – 10 ng/g plasma.     

Effects of chronic lithium, amitriptyline and mianserin on glucoregulation, corticosterone and energy balance in the rat

Major negative side-effects reported for mood-stabilizing and antidepressant drugs in humans are excess weight gain and carbohydrate craving. The aim of the present study was to establish whether the rat could usefully be employed in investigation of these phenomena. Three experiments investigated the effects of chronic lithium (40 mg/kg LiCl), amitriptyline (2.5 mg/kg), mianserin (2.5 mg/kg) and saline administration (15-20 days, one subcutaneous injection/day) on body weight, food intake and fluid intake. Water and food cubes were provided in all experiments. Additionally available, as separate fluid sources, in Experiment 2 were 24% sucrose and 0.6% saccharin and in Experiment 3, 0.6% saccharin. Blood was collected for plasma glucose and insulin determinations 20-24 hours after the final injections. Lithium administration resulted in a marked increase in weight gain but only if both sucrose and saccharin were available (Experiment 2). Saccharin intake was increased with lithium treatment as was total caloric intake with sucrose available. Amitriptyline induced a sweetness craving; however, weight gain was somewhat depressed with just cubes available (Experiment 1) and only normalised by the additional availability of sucrose and saccharin (Experiment 2). With amitriptyline, total caloric intake was never different from controls. Weight gain was slightly suppressed and caloric intake slightly elevated by mianserin but importantly the two effects combined for a decrease in metabolic efficiency which was particularly exaggerated under the condition of carbohydrate availability (Experiment 2). Lithium and amitriptyline both produced hyperinsulinemia with normoglycemia whether or not the rate of weight gain was changed and whether or not intake was increased. Corticosterone levels were elevated by all drug treatments in Experiment 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n=17) and amitriptyline (AT, n=16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiels for uptake blockade and anticholinergic potency for these two compounds.     

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.     

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.     

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.     

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.