Plasma levels and antidepressive effect of imipramine.

The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin-layer chromatography. Individual variations in plasma concentration were 20- to 30-fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (HRS post-treatment score less than 8) had plasma concentration of imipramine greater than or equal to 45 mug/L, and desipramine greater than 75 mug/L, whereas the 12 patients not responding satisfactorily (post-treatment score on HRS greater than or equal to 8) all had concentrations of imipramine or desipramine or both below these limits.

Imipramine metabolites in blood of patients during therapy and after overdose.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants.

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.

Relevance of tryptophan and tyrosine availability in endogenous and 'non-endogenous' depressives treated with imipramine or clomipramine.

This study was performed on 65 depressed in-patients who were included in previously reported trials of imipramine and clomipramine. Before and during treatment, blood samples were collected for estimation of the availability of tryptophan and tyrosine by measurement of their plasma ratios to competing amino acids, and for determination of plasma steady-state concentrations of imipramine, clomipramine and their demethylated metabolites. The patients were classified as endogenous or 'non-endogenous' depressives by means of diagnostic rating scales, and therapeutic efficacy was evaluated by means of the Hamilton rating scales. Neither imipramine nor clomipramine increased the availability of tryptophan or tyrosine. Three biochemical regions were defined: a low region including mostly patients with subnormal availability of both tryptophan and tyrosine, a medium region, and a high region including mostly patients with supernormal precursor availabilities. Endogenous depressives showed about the same biochemical distribution as controls whereas there tended to be a proportionately higher number of 'non-endogenous' depressives within the low region. Patients in the low region, irrespective of diagnostic classification, improved faster and more on imipramine than patients in the medium and high regions with comparable plasma drug levels. Patients on clomipramine tended to show a relationship between precursor availabilities and clinical response but no definite conclusion could be drawn from these data. The results suggest that determination of the pre-treatment tryptophan and tyrosine availability may be superior to diagnostic classification in predicting response to imipramine. The possible mode of action of tricyclic antidepressants is briefly discussed.

The Diagnostic Melancholia Scale (DMS): dimensions of endogenous and reactive depression with relationship to the Newcastle Scales.

The two diagnostic Newcastle Scales for depression have been evaluated in a drug trial with antidepressants. By use of latent structure analysis (Rasch models) it was found that two dimensions are necessary for describing the diagnosis of depression, one for endogenous features and one for reactive features. Of the depressed patients 50% had a pure endogenous depression, 14% had a pure reactive depression, 32% had mixed endogenous and reactive depression, and 4% had uncertain diagnosis. In the pure endogenous depression group 77% had a monotonically non-decreasing improvement curve during treatment whereas in the other diagnostic categories around 50% had such an improvement.

[Quality assurance in psychiatry]. / Kvalitetssikring i psykiatrien.

The need for ensuring quality in psychiatry and the elements in the structure, process and outcome are described together with the terminology employed in this field. The internal and external methods of ensuring quality in psychiatry are mentioned and an example of "time monitoring" of the physician's time devoted to patient-related work in a psychiatric department is presented. This example shows that each patient can obtain ten minutes of direct contact during each working day at the very most. It is concluded that it is possible to establish standards for structure and the processes employed in treatment of psychiatric patients but that it is much more difficult to establish standards for the outcome. Establishment of quality ensurance programmes at local level is recommended but The Public Health Board, Danish Psychiatric Association and possibly the consumers' association should develop and assess the necessary methods.