The involvement of the World Psychiatric Association in the issue of the political abuse of psychiatry.

This article provides a historical account of the abuse of psychiatry for political purposes and the involvement of the World Psychiatric Association (WPA) in this issue. The article focuses, particularly, on the developments from 1983 to 1989, which in many ways was crucial and determined the future of the WPA. The authors (the first, the President and the second, the Treasurer of the WPA during this period) pay tribute to Dr. Fini Schulsinger, who served as Secretary General. Through his eminent administrative capabilities, his profound understanding of ethical problems and his devotion to the basic principles of the WPA, he has substantially contributed to successfully overcoming a deep crisis with considerable impact on the identity and the moral foundations of the psychiatric profession.

Therapeutic potentials of recently introduced antidepressants. Danish University Antidepressant Group.

The DUAG studies showed that in well-designed and rigorously executed multisite drug trials three representatives (citalopram, paroxetine, and moclobemide) from two classes of recent antidepressant drugs were less effective than the standard reference drug, clomipramine. The most important reasons for the superiority of clomipramine was probably that clomipramine was given in a high and fixed dose of 150 mg per day throughout the entire treatment period and that patient compliance was ensured through drug monitoring. When the DUAG studies are compared with "no difference" studies, the difference between DUAG and others lies not so much in a different efficacy of the test drugs but in the efficacy of the reference drugs, where clomipramine in the DUAG studies was more effective than reference tricyclics in most other studies with flexible dose regimens. A relatively high rate of adverse drug reactions with clomipramine administered in high and fixed doses was probably due to a considerable interindividual variability in the pharmacokinetic properties. (Gram 1990), and the development of side effects may be predicted and prevented when better knowledge of plasma concentration and dose-response relations for classical tricyclic antidepressants allow individual dose adjustments. Such studies are under way with in the DUAG. The results of such studies may reduce the need for new antidepressants which, although less toxic than the classical tricyclics, may prove to be also less potent. The DUAG studies were performed in hospitalized, moderately to severely, endogeneously depressed adult patients and conclusions from the DUAG studies about the superiority of clomipramine over three recent antidepressants cannot readily be generalized to cover less homogeneous groups of outpatients with milder depression.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

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.

Biochemical and diagnostic classification and serum drug levels: relation to antidepressive effect of imipramine.

The relationship between clinical effect of imipramine (IP) in 39 depressed patients and biochemical distinction, serum drug levels, and diagnostic classification was investigated retrospectively. Based on pretreatment plasma ratios of tryptophan and tyrosine to competing amino acids, which reflect the availability of the precursor amino acids to the brain, the patient sample was separated in two halfparts. The one group with low net availability of tryptophan and tyrosine improved significantly more than the other group with comparable mean serum drug levels. In the former group there was no association between clinical improvement and serum drug levels, whereas in the latter group the patients with serum IP plus desipramine (DMI) above 180 ng/ml improved significantly more than patients with lower levels. There was an indication that a serum ratio of IP:DMI below 0.2 was associated with a poor response. Patients classified as nonendogenous depressives by means of the Newcastle II scale showed about the same response pattern as endogenous depressives with comparable plasma amino acid profiles and serum drug levels. Based on amino acid patterns and serum drug levels only half of the patients received an optimal therapy on the applied schematic dosage schedule. Thus, biochemical classification rather than diagnostic may be a useful remedy for the adjustment of serum IP plus DMI to appropriate levels in individual depressives.

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.

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.

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 Hamilton depression scale. Evaluation of objectivity using logistic models.

The consistency of the Hamilton Depression Scale (HDS) as a measure of the severity of depressive states has been examined when the scale was used weekly during a trial when imipramine. By use of logistic models (Rasch) the consistency of the HDS has been considered across patient-variables as age, sex, plasma levels of imipramine, and diagnosis. The results showed that the original 17-item HDS was without adequate consistency, i.e. the total score of the sample of items was no one-dimensional measure of depressive states. However, a melancholia subscale of the HDS contained items the total of which can be used to compare patients quantitatively, although in some part of the analysis one of these items showed ceiling effect. It was concluded that the melancholia subscale (containing the items depressed mood, guilt, work and interests, retardation, psychic anxiety, and general somatic symptoms) can form the basis for further improvements in the field of quantitative rating scales for depressive states.