Clomipramine treatment of obsessive-compulsive disorder. I. A controlled clinical trial.

The effect of clomipramine hydrochloride in severe obsessive-compulsive disorder (OCD) was compared with that of nortriptyline hydrochloride and placebo in a five-week randomized, double-blind trial. Clomipramine, but not nortriptyline, was superior to placebo in interview-based ratings of severity of OCD. The effect was not clear-cut until after five weeks of treatment. When clomipramine was given openly to 22 patients after the end of the controlled trial, half of the patients responded to the drug. The response could not be predicted from severity or duration of illness, sex or age of the patient, or presence or absence of secondary depressive symptoms. The amelioration with clomipramine was not sustained if the drug was withdrawn.

[Use of antidepressants: pharmacokinetic basis (author's transl)]. / Utilisation des antidépresseurs: bases pharmacocinétiques.

It is evident from a number of studies that "antidepressants" may be effective in the treatment of various depressive disorders, but also that failures are quite common. The reasons are manifold, but an important source of variation is the pharmacokinetics of these drugs. An adequate concentration of the drug at the cerebral receptors is a reasonable prerequisite for success. This concentration is likely to be reflected by the plasma level of the drug that may display great variations in different individuals receiving the same dosage, mainly due to variations in drug metabolism. The metabolism of the drug depends both on genetic factors and on induction by other drugs such as barbiturates. Whereas most side effects have a fairly simple, linear relation to the blood level, this does not hold true for all drugs as regards their therapeutic effect. Nortriptyline and possibly also mianserin show a curvilinear relation between level and therapeutic outcome. The effect is optimal within a certain concentration range, worse with both lower and with higher concentration. Monitoring treatment by means of measuring blood concentration may thus be desirable in certain situations. -With dimethylated drugs the effects may be complicated if the drug itself and some metabolite act on different transmittor systems. This holds true for, e.g., chlorimipramine and zimelidine. However, the clinical implications are still obscure.

Experimental studies of the therapeutic action of electroconvulsive therapy in endogenous depression. The role of the electrical stimulation and of the seizure studied by variation of stimulus intensity and modification by lidocaine of seizure discharge.

Three methods of electroconvulsive therapy (ECT) were compared in respect of therapeutic effect in 69 attacks of endogenous depression in 65 patients, not previously treated by ECT during the actual period of illness. The treatments were given under barbiturate narcosis, with full muscular relaxation, administration of oxygen and electroencephalographic recording of the seizure discharge. In two methods grand mal seizures were evoked by supraliminal (A) and liminal stimulation (B), in the third (C) lidocaine (3 mg/kg i.v.) was given before the application of liminal stimulation. The seizure discharges in C were markedly shortened and their pattern modified, while between A and B the duration and pattern of the seizures were similar (Table 1). The patients were referred to the three treatments at random and the groups may be regarded as having a similar prognosis (Table 2-5, 7). The therapeutic outcome was estimated by rating several depressive symptoms according to a rating scale worked out for the purpose. The rating was performed before treatment, one week after the fourth treatment (a treatment pause was then made) and one week after the completed series. To obtain more reliable measures the scores for the various symptoms were added together to form a total score, which was then divided into a depression score and a retardation score, presumably measuring mainly depressive mood and psychomotor retardation. Differences in rating scores on two rating occasions were taken as measures of improvement. In addition, a global rating of improvement was made. The rating procedure was double blind. The principal results were: 1. After four treatments (three patients who recovered after three treatments included) the degree of improvement was in the rank order ABC with significant group differences for a few scores. After the completed series of treatments improvement in groups A and B did not differ significantly whereas in group C it was significantly smaller for some scores (Table 9). 2. The total number of treatments was significantly higher in group C than in group A and B, which did not differ significantly between themselves (Table 10). 3. A measure of therapeutic efficiency, improvement per treatment, was computed by dividing the degree of improvement as obtained from the differences in the combined scores and from the global score of improvement, by the number of treatments. After four treatments the improvement per treatment was highest in group A and lowest in group C, although in the comparisons AB and BC most differences did not reach significance. After the completed series the improvement per treatment did not differ significantly in groups A and B whereas in group C it was significantly less (Table 10). 4. In comparison with groups A and B, the total duration of seizure discharges was significantly shorter in group C both after four treatments and, in spite of the higher number of treatments, after the completed series. The improvement per second of seizure discharge was not significantly different in the groups although there was a tendency to a lower effect per second in group B (Table 11). It is concluded from these results that shortening of the seizure discharge decreases the therapeutic efficiency of ECT. Increase of the stimulus intensity, which apparently does not change the seizure discharge, possibly gives a more rapid therapeutic response but does not change the final degree of improvement or the number of treatments required to reach it. The depression-relieving effect of ECT is bound to seizure activity and not, or only slightly, to other effects of electrical stimulation.

Piracetam-induced improvement of mental performance. A controlled study on normally aging individuals.

A double-blind, intra-individual cross-over comparison of the mental performance of 18 aging, non-deteriorated individuals during two 4-week periods of piracetam (1-acetamide-2-pyrrolidone) and placebo administration was performed using conventional and computerized perceptual-motor tasks. In a majority of these tasks the subjects did significantly better when on piracetam than on placebo, a finding consistent with ratings completed by two independent observers. The findings indicate new avenues for the treatment of individuals with reduced mental performance possibly related to disturbed alertness--a neglected group of psychiatric conditions.

Relationship between plasma level and therapeutic effect of nortriptyline.

The relationship between plasma concentration of nortriptyline and therapeutic effect after two weeks' treatment with the drug was investigated in 29 psychiatric inpatients. Endogenous depression was diagnosed in all patients. Amelioration of depressive symptoms was estimated as reduction in score on a rating scale, based on a psychiatric interview. Amelioration was not correlated to the patient's sex or age. There was a curved relationship between plasma level of nortriptyline and therapeutic effect. Amelioration was most pronounced in the intermediate plasma level range (50-139 ng nortriptyline/ml plasma) and was slight both at lower and at higher plasma levels. This type of relationship may be due to the dual action of tricyclic antidepressants which has been found in animal experiments. On larger dosages a phenothiazine-like blockade of the monoaminergic receptor is added to the blockade of monoamine reuptake thought to be related to the antidepressant action of the drugs.THIS STUDY THUS SUGGESTS TWO POSSIBLE REASONS FOR A THERAPEUTIC FAILURE WITH NORTRIPTYLINE: a too low or a too high plasma level. The large individual variation in the pharmacokinetics of the tricyclic antidepressants makes prediction of plasma level from dosage in a given individual virtually impossible without knowledge of rate of elimination and apparent volume of distribution. Hence monitoring plasma levels may be a way to increase the efficacy of treatment with these drugs.

Does piracetam counteract the ECT-induced memory dysfunctions in depressed patients?

A double-blind, intra-individual cross-over comparison of the effect of piracetam on retrograde memory impairement as measured by the KS memory test battery was performed in connection with second and third Bi-ECT in 18 patients diagnosed as suffering from depression. The seizure duration and the post-ECT EGG patterns were examined visually and the post-ECT confusion time was measured. Piracetam was given orally in the dose of 4.8 g/day for 3 days. No significant effects were obtained on memory scores, electrical stimulus duration, EEG pattern or post-ECT confusion time. The findings may indicate that the protective effect of piracetam shown in animal electroconvuslive stimulation (ECS) is due to a counteraction of the disturbing effect of hypoxia on memory functions. It is concluded that more information is needed as regards the pharmacokinetics and the mode of action of the drug.

Correlation of subjective side effects with plasma concentrations of nortriptyline.

Plasma levels of tricyclic antidepressant drugs vary considerably between individuals receiving the same amount of drug. The bearing of this variation on the occurrence of subjective side effects was investigated in 40 psychiatric inpatients with depressive disorders. Plasma levels were determined before and during four weeks of treatment with nortriptyline 50 mg. three times a day and patients were rated for subjective side effects, the assessors being unaware of the plasma levels of the drug.Plasma levels varied widely between individual patients, but in any given patient the plasma level tended to be constant over a period of time. The side effects of nortriptyline diminished significantly with time and were in most cases absent during the fourth week of treatment. There was a significant positive correlation between plasma level of nortriptyline and subjective side effects.The steady-state plasma level of a drug which is metabolized is usually a more important determinant for its effect than dosage, since it reflects the amount of drug available for biological action. Very high plasma levels of nortriptyline should presumably be avoided, since there is no evidence that they are needed for therapeutic effect and they are potentially harmful.