Amitriptyline pharmacokinetics and clinical response: I. Free and total plasma amitriptyline and nortriptyline.

A group of 30 patients suffering from endogenous depression was treated with 150 mg amitriptyline (AT) for 21 days. Depression ratings and determinations of total and free plasma AT and nortriptyline (NT) were performed weekly. No correlation between clinical improvement and any of the biochemical parameters was found. Thus, this study does not support the existence of a therapeutic window for AT. A highly significant correlation was calculated between free and total AT and free and total NT, and also between the free fractions of AT and NT; moreover, age correlated significantly and positively with total plasma AT, but not with NT, and negatively with the free fractions of both AT and NT. The absence of correlation between clinical improvement and pharmacokinetic parameters is discussed for its possible significance. The finding that responders are also found in patients with "low" levels of antidepressants (corroborating the pharmacokinetic and pharmacodynamic data obtained in animals submitted to a long-term treatment with antidepressants) suggests that the concept of the need for steady-state levels with low fluctuations should be re-examined. In the light of these results the clinical effectiveness of treatment with higher drug doses, administered at larger intervals, in order to produce high amplitude fluctuations of the antidepressant should be studied.

Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: an electrophysiological investigation.

Ten healthy volunteers were injected i.v. with 5 mg Ro 15-1788, a specific benzodiazepine antagonist, or placebo in a double-blind randomised design. In the EEG, Ro 15-1788 led--with some topographical variations--to a diminution of theta and alpha power, an increase of alpha mean frequency and a decrease of delta mean frequency. In auditory evoked potentials, the N1P2 and P2N2 amplitudes decreased. The electrophysiological changes induced by Ro 15-1788 are consistent with a central stimulant action. Ro 15-1788 induced some slight behavioural and subjective changes.

Effects of a benzodiazepine antagonist on the diazepam-induced electrical brain activity modifications.

Brain electrical activity changes induced by Ro 15-1788, an antagonist of central benzodiazepine effects, were investigated in 10 normal subjects. The diazepam-induced sedation, as ascertained by spontaneous EEG, was rapidly reversed after an intravenous injection of 5 mg Ro 15-1788. There appeared to be a good correlation between the EEG and evoked responses modifications; the decrease of the amplitude of the N2 wave may reflect an increase of alertness.

On the nosology of severe psychiatric post-partum disorders. Results of a catamnestic investigation.

A group of 57 women, who had been hospitalised for puerperal psychiatric disorders from 1958 to 1977, were reexamined in 1982. The aim of the study was to determine the proportion of patients who had suffered from nonpuerperal psychotic relapses or other subsequent psychopathology, to define the sample diagnostically, taking into account progress in classification, to characterize the so far relatively neglected later course of illness, and to establish criteria related to relapse and global clinical outcome. Of these patients 65% had at least one nonpuerperal relapse, only 25% remained free of later psychopathology, but the global outcome was favorable or relatively favorable in many cases. Of the patients who had had nonpuerperal relapses 43% were classified as suffering from affective psychosis, as many as 38% from schizoaffective psychosis, and only 19% from schizophrenia. Schizoaffective psychosis seems to be particularly liable to be provoked by childbirth. No major evidence was found that endogenous psychoses with puerperal onset and nonpuerperal relapses have a course of illness different from that of the corresponding diagnostic category in general. Cases with exclusively puerperal decompensations seem to be nosologically independent from the traditionally recognized endogenous psychoses. Characteristics strongly related to nonpuerperal relapses were a family history of psychosis and the occurrence of psychotic episodes before the index episode. Puerperal relapses occurred at a much higher rate in patients who also had nonpuerperal relapses than in patients without.

[Clinical characteristics of a representative group of hospitalized depressed patients]. / Caractéristiques cliniques d'un groupe représentatif de patients dépressifs hospitalisés.

In order to define some principal clinical characteristics of the hospitalised depressives, the authors have examined a group of 100 depressed patients consecutively admitted to the Psychiatric University Clinic of Lausanne. The clinic is at the same time a sector hospital. The depressives constituted 21% of all hospitalised patients. The number of depressives admitted during the duration of the study (6 months) permitted to calculate a hospitalisation rate of 86 patients per 100 000 inhabitants and per year. The 100 patients were subclassified in patients with a short depressive reaction, neurotic depressives, and endogenous depressives. Each of the 3 subgroups had about the same size. A modified version of the ICD 9 was used for the diagnostic classification. As a whole, the patients showed serious psychiatric manifestations and the majority presented suicidal tendencies. Besides, there were found characteristics which are not considered to be associated with depressions in general: an elevated proportion of unmarried persons in the total group, psychopathic traits among the reactive and neurotic depressives, and a considerable proportion of parental loss in early childhood in these two last mentioned subgroups. Furthermore, an accumulation of chronic and therapy resistant cases was observed in the group of neurotic depressives. A third of the endogenous depressives had been resistant to the ambulatory antidepressive treatment; a part of these patients responded well to the treatment in the hospital.

On the relationship between free plasma and saliva amitriptyline and nortriptyline.

Conflicting results on the correlation of tricyclic levels in plasma and saliva have raised doubts about the clinical usefulness of monitoring these drugs in the latter body fluid. However, saliva drug levels may reflect the free plasma concentration, which possibly determines its level in the brain. In two groups of depressive patients, the evolution was studied of the levels of amitriptyline and nortriptyline in plasma (as free and total) and in saliva, after the administration of amitriptyline. The results show a poor correlation between total plasma and saliva concentration of amitriptyline and nortriptyline, respectively. Levels of both tricyclics in saliva exceed by far those measured in plasma dialysate. However, the relationship is such that free plasma concentrations may be predicted from those measured in saliva, if one takes into account saliva pH at the moment of collecting the sample.

Relationship between plasma-levels of chlorpromazine and effects on EEG and evoked potentials in healthy volunteers.

The effect of chlorpromazine (CPZ) was studied at four different doses in a group of 10 normal subjects. Blood levels of CPZ were assayed by gas chromatography and showed wide interindividual variations. Spontaneous brain electrical activity (EEG) was recorded from 8 leads and submitted to spectral analysis. Evoked responses (ER) to flashes, pattern reversals and clicks were averaged, and measured by their amplitude and variability. Several subjects presented marked side-effects (responders, R) and showed differences in many EEG parameters with respect to subjects without side-effects (non-responders, NR). A cluster analysis permitted to distinguish very clearly these two groups of subjects. The differences in the effects of CPZ between the R and NR groups involved mainly EEG, and appeared with a systematic topography over the scalp. Within the R group, many differences were observed as a function of the dose of CPZ; they consisted mainly in a decrease of alpha and an increase of theta activity in the EEG, decrease of amplitude and increase of variability in the ER measures. These modifications had also a typical topography over the scalp. Finally, many variables of EEG (relative power only) were correlated with plasma level of CPZ, while no such correlation appeared for ER. These results are discussed in terms of individual sensitivity to drugs, relationships between EEG parameters and plasma level, and topographical differences in the effect of CPZ.