Pilot study of PK 11195, a selective ligand for the peripheral-type benzodiazepine binding sites, in inpatients with anxious or depressive symptomatology.

PK 11195 is a selective ligand for the peripheral-type benzodiazepine binding sites which exhibits anti-conflict activity in animals. In a pilot open study, PK 11195 was administered to 10 psychiatric inpatients characterized by a rating of at least "moderate" for the item "felt loss of vitality" and a rating of at least "moderate" for the items "anxiety" and/or "inhibition of drive" from the psychopathological scale of the system developed by the Association for Methodology and Documentation in Psychiatry (AMDP). The duration of the study was two weeks, with an initial daily dose of 200 mg of PK 11195 which could be increased up to 400 mg. Patients were assessed weekly using the psychopathological and somatic AMDP scales and at days 0, 4, 7, and 14 using the Hamilton anxiety scale and a checklist of symptoms and side-effects. The results showed significant improvement in the AMDP factor scores related to somatic complaints, depression, anxiety, apathy-retardation, and psycho-organic symptoms. However, anxiolytic activity, confirmed on the Hamilton anxiety scale, remained moderate and reached maximum effect after one week. No side-effects, drowsiness in particular, were reported. This study therefore suggests a potential beneficial activity of PK 11195 on anxiety and inhibition, which merits further investigation in controlled studies.

Blunted response of growth hormone to clonidine and apomorphine in endogenous depression.

We measured the growth hormone (GH) response to clonidine (an alpha-2-adrenergic agonist) and to apomorphine (a dopaminergic agonist) in 15 major endogenous and 15 minor depressive in-patients matched for gender and age. Results showed a significantly smaller GH response in the major depressives to both clonidine (P less than 0.01) and apomorphine (P less than 0.001). No significant difference existed between the two groups with regard to changes in blood pressure and pulse rate during either test. While major depressives showed a trend toward smaller sedative side-effects than minor depressives after clonidine, they showed significantly smaller sedative and gastro-intestinal side-effects after apomorphine. No significant correlation was present either in the major depressive or in the minor depressive group between the GH responses following clonidine and apomorphine challenges. These results support the hypothesis of both noradrenergic and dopaminergic neurotransmitter disturbances in major depression, with individual variability with regard to those biochemical anomalies.

[Assessment of the clinical activity of fluoxetin (Prozac) according of the "Stars of Liège" model]. / Evaluation de l'activité clinique de la fluoxétine (Prozac) selon "les étoiles de Liège".

Ten psychiatrists have independently rated the clinical profile of fluoxetin (Prozac) at the daily dose of 20 mg according to a "Stars of Liège" model comprising three parameters of therapeutic activity (antidepressant, psychostimulant and anxiolytic) and three parameters of side-effects (anticholinergic, sedative and hypotensive). Each parameter, graduated from 0 to 5 (no, very weak, weak, moderate, potent, very potent effect) was rated by each investigator according to his personal experience with at least 10 patients. Mean ratings given to fluoxetine show a moderate antidepressant effect, equal to amitriptyline (Rédomex, Tryptizol 75 mg/d, clomipramine (Anafranil 75 mg/d and nialamide (Niamide 100 mg/d, weak psychostimulating and anxiolytic effects, a very weak sedative effect and a lack of anticholinergic and hypotensive effects. Digestive side-effects of moderate intensity were also noted as well as a very weak anorexia. The important variability between investigators in the rating of the clinical profile of fluoxetine suggests that more experience is needed in order to define better its physiognomy.

Neuroendocrine evaluation of catecholaminergic neurotransmission in mania.

Several lines of evidence suggest catecholamine overactivity (noradrenergic and/or dopaminergic) in mania. We studied the growth hormone (GH) response to clonidine (an alpha-adrenergic agonist) and apomorphine (a dopaminergic agonist) in seven inpatients meeting Research Diagnostic Criteria for mania. They had been completely drug free for at least 3 months before the neuroendocrine procedures and were age- and sex-matched to seven major depressive and seven minor depressive inpatients, drug free for at least 2 weeks. GH was assayed every 20 min for 40 min before and 120 min after either clonidine (0.15 mg i.v.) or apomorphine (0.5 mg s.c.), with an interval of at least 2 days between the tests. The three groups differed significantly in the GH peak response: after clonidine (mean +/- SD), 3.2 +/- 2.4 ng/ml in manics, 3.2 +/- 2.4 ng/ml in major depressives, and 13.2 +/- 8.7 ng/ml in minor depressives; after apomorphine, 10.5 +/- 7.4, 3.2 +/- 1.9, and 26.9 +/- 15.8, respectively. While there were significant differences between manics and minor depressives and between major and minor depressives after both clonidine and apomorphine, manics did not significantly differ from major depressives on either test. These results do not provide neuroendocrine support to the catecholaminergic hypothesis of manic disorders.

Diagnostic performance of basal free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) ratio in endogenous depression: comparison with the dexamethasone suppression test.

We assessed the 8:00 AM ratio of free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) in 56 endogenous depressive inpatients and in 22 normal volunteers. A ratio higher than 40 was associated with a diagnostic sensitivity for endogenous depression of 75%, a specificity of 95.5%, and a diagnostic confidence of 97.7%. These diagnostic results were at least equivalent to the Dexamethasone Suppression Test (DST) using a cortisol cut-off limit of 5 micrograms/dl. This may thus represent a simpler procedure than the DST in the diagnostic analysis of endogenous depression.

[The Newcastle Index for the diagnosis of endogenous depression. Comparison with the Research Diagnostic Criteria for major depression]. / L'index de Newcastle pour le diagnostic de dépression endogène. Comparaison avec les Critères de Diagnostic pour la Recherche de dépression majeure.

The Newcastle index comprises 10 items (with a positive or negative score) the sum of which enables us to separate endogenous and neurotic depressive patients. We applied this index to a sample of 41 depressive inpatients who met Research Diagnostic Criteria (RDC) for major depression. According to Newcastle index, 20 patients were considered to be endogenous and 21 to be neurotic. There was no significant difference between the two groups with regard to sex distribution and mean age. The distribution of scores suggested a trend toward bimodality. Endogenous depressives exhibited higher severity level than neurotic depressives, as shown by the total score on the Hamilton depression scale as well as the scores on various items related to depressive mood, guilt, decreased activity, psychomotor disturbances, genital symptoms, helplessness, hopelessness, and worthlessness. This higher severity level was confirmed by the higher frequency of two symptomatic criteria of major depression among endogenous depressives as compared to neurotic depressives: psychomotor and memory disturbances. Moreover, endogenous depressives defined by Newcastle index were more frequently of primary, endogenous, agitated and simple RDC subtypes whereas neurotic depressives were more frequently of secondary and situational RDC subtypes. Therefore, the results of this preliminary study suggest that the Newcastle index may enable us to define two subtypes of depressive patients characterized by different symptomatic severity levels.

Intranasal oxytocin in obsessive-compulsive disorder.

A 55-year patient with obsessive-compulsive disorder showed clear improvement during 4 weeks of treatment with intranasal oxytocin compared to 4 weeks of intranasal placebo. This improvement was concurrent with the development of severe memory disturbances, supporting the amnestic properties of the peptide. However, the patient also developed psychotic symptoms and a marked decrease in plasma sodium and osmolality, which may have masked the obsessive symptomatology. This case highlights the need for careful monitoring in long-term oxytocin therapy.

[Novel comparative profile of the clinical activity of antidepressive agents]. / Une physionomie comparée originale de l'activité clinique des antidépresseurs.

In order to develop practical criteria to guide in the selection of antidepressant medication according to depressive symptomatology, we propose a graphical representation of the clinical activity of 24 antidepressants according to a "star" model. Six parameters have been evaluated from 0 to 5 in comparison to reference drugs (rated 5) by 11 independent "blind" psychiatrists expert in pharmacotherapy. Three parameters were used as measures of therapeutic activity: antidepressant, psychostimulant, and anxiolytic, with iproniazide 75 mg/d, metamphetamine 15 mg/d, and diazepam 20 mg/d as reference drugs respectively. Three additional parameters assessed the level of side-effects: anticholinergic, sedative, and hypotensive, with atropine 0.75 mg/d, phenobarbital 200 mg/d, and iproniazide 75 mg/d as reference drugs respectively. The defined dose represented the standard maintenance daily dose for depressive outpatients. Mean values for each parameter, rounded off to the closest number, were used for the graphical representation. Results showed an excellent agreement among evaluators for the clinical profile of classical tricyclic and MAOI antidepressants, but serious divergences for the more recent drugs (e.g., viloxazine and mianserine), possibly reflecting more atypical or more variable clinical profile of these compounds.

Diagnostic performance of the thirty-four hour dexamethasone suppression test.

The performance of the dexamethasone suppression test (DST) in the diagnostic confirmation of endogenous depression was compared according to two times of blood collection--1600 hr on day 2 (usual sample) and 0800 hr on day 3 (34 hr after dexamethasone intake)--in 14 endogenous depressives and in a control group of 17 psychiatric inpatients with other diagnoses. For the day 2 (1600 hr) sample, a 5 micrograms/dl cortisol concentration represented the best cut-off score, with sensitivity of 57% specificity of 88%, and diagnostic confidence of 80%. For the day 3 (0800 hr) sample, the best cut-off score was 20 micrograms/dl, with the same sensitivity (57%) but there was a decrease of both specificity (to 76%) and diagnostic confidence (to 67%). The mean cortisol levels were much higher on day 3 than on day 2, suggesting that the inhibitory activity of dexamethasone was no longer present.

Use of saliva cortisol in the dexamethasone suppression test.

In a sample of 26 inpatients (15 primary endogenous depressives and a heterogeneous comparison group of 11 psychiatric patients), results of the dexamethasone suppression test (DST) for endogenous depression were compared when cortisol was measured in plasma (total and free) and in saliva. Results showed a close linear relationship among plasma total and free cortisol, plasma total cortisol, and saliva cortisol, and between free plasma and saliva cortisol. A saliva cortisol cutoff point of 70 ng/dl achieved the same sensitivity (67%), specificity (91%), and diagnostic confidence (91%) as the best cutoff scores of plasma total cortisol (5 micrograms/dl) and plasma free cortisol (0.15 microgram/dl). These results suggest that saliva cortisol, which directly reflects the biologically active fraction of cortisol, can be used as a reliable and more practical index in the DST, especially in outpatients.

Self-reports of anxiety level and EEG changes after a single dose of benzodiazepines. Double-blind comparison of two forms of oxazepam.

A new formulation of oxazepam especially designed to increase the speed of absorption and eliminate the need to use water (freeze-dried dosage formulation; FDDF) was compared in double-blind and crossover conditions with the standard tablets of the same compound. 5 inpatients with generalized anxiety disorder received at 1-week intervals a single 30 mg dose of one of the compounds. Every 8 min for 96 min after drug intake, they completed a battery of visual analogue scales and had an EEG recording with computerized spectral analysis. Results showed a significantly more rapid onset of activity of FDDF oxazepam for both the self-reports of anxiety level (p less than 0.005) and the specific beta 2 EEG changes (p less than 0.0001), which were significantly correlated (r = -0.73; p less than 0.01). Moreover, all patients rated FDDF oxazepam as having faster onset of action in clinical change than regular tablets (p less than 0.05). This study shows the value of visual analogue scales, pharmaco-EEG, and crossover design in well-selected anxious inpatients in substantiating clinical differences between anxiolytic pharmacotherapies.

[The necessity for standardized diagnosis in research in biological psychiatry. Attempted integration of "Research Diagnostic Criteria" into the AMDP system]. / De la nécessité du diagnostic standardisé dans la recherche en psychiatrie biologique. Essai d'intégration des "Research Diagnostic Criteria" dans le système AMDP.

Standardization of diagnosis is an essential preliminary in the clinical research in biological psychiatry. Between the different systems of nosographical selection, Research Diagnostic Criteria (RDC) are the most internationally diffused. After having recalled the spirit of RDC, we have looked for seven major illnesses (major and minor depressive disorders, endogenomorphic major depressive disorder, schizophrenia, manic disorder, panic disorder and generalized anxiety disorder) equivalents of RDC criteria in psychopathological and somatical items of AMDP system. With a minimum of modifications (adjonction of some reserve items for each illness), AMDP scales could become compatible. The verification of this theorical equivalence secondly makes it a duty to use jointly RDC and AMDP scales and to analyse both of them separately. After this methodological control, patients who meet RDC criteria could be automatically selected from AMDP scales.