Defective protein kinase C-mediated actions in cystic fibrosis neutrophils.

Neutrophils from cystic fibrosis (CF) patients have been shown previously to be defective in their response (beta-glucuronidase exocytosis, NADPH oxidase activation) to the chemotactic peptide FMLP. In this work, we attempted to identify the defective step in this response. We showed that stimulated CF and control neutrophils do not differ in the formation of inositol phosphates. On the other hand, direct stimulation of protein kinase C with phorbol myristate acetate (PMA) revealed a subnormal stimulation of beta-glucuronidase exocytosis in CF neutrophils. Furthermore, retroinhibition exerted by PMA-activated protein kinase C on stimulated inositol phosphates or on beta-glucuronidase exocytosis was marginal or absent in CF neutrophils, whereas it was significant in the case of control neutrophils. Our observations suggest that the CFTR gene is expressed in neutrophils and is involved in protein kinase C-mediated actions.

Alteration of the N-formyl-methionyl-leucyl-phenylalanine-induced response in cystic fibrosis neutrophils.

In order to determine whether cystic fibrosis neutrophils are affected in their secretory functions, lysosomal enzyme release and chemiluminescence (light emission from cells) were assayed in patients' cells and compared with those in normal control cells. We observed a decreased response of cystic fibrosis neutrophils in beta-glucuronidase release and chemiluminescence after stimulation by N-formyl-methionyl-leucyl-phenylalanine. There was no significant correlation of these results with the clinical score nor with the medical treatment. On the other hand, responses to the calcium ionophore A23187 and to opsonized zymosan showed no significant difference between normal and cystic fibrosis subjects in lysosomal enzyme release. N-formyl-methionyl-leucyl-phenylalanine receptor alterations did not seem involved in the observed effect as demonstrated by Scatchard plot analysis of N-formyl-methionyl-leucyl-phenylalanine binding to these receptors. These results clearly demonstrate a difference between normal and cystic fibrosis neutrophils in release and chemiluminescence responses to N-formyl-methionyl-leucyl-phenylalanine stimulation, a difference that might be located in the plasma membrane as both responses are membrane dependent.

Extrapyramidal signs following zimelidine overdose.

A 35-year-old woman with depression attempted suicide by taking an overdose of zimelidine (5 g), which was confirmed by zimelidine and norzimelidine plasma levels. Physical examination and repeat EKGs performed 2, 6, 9, and 12 hours later showed no alteration in her level of consciousness and only a slight increase in QT duration. However, the patient exhibited a distinct extrapyramidal syndrome, a finding consistent with animal data suggesting that zimelidine may possess some dopamine-receptor blockade properties.

[Value of the sleep EEG as a biological marker of depressive states. Comparison with 3 neuroendocrine tests]. / Intérêt de l'EEG de sommeil en tant que marqueur biologique des états dépressifs. Comparaison avec trois tests neuro-endocriniens.

In a sample of 12 endogenous depressive inpatients (8 primary and 4 secondary depressives), we compared the diagnostic usefulness of REM latency (recorded during at least 4 consecutive nights) with 3 neuroendocrine tests: dexamethasone suppression test and GH response after clonidine (a alpha-adrenergic agonist) and apomorphine (a dopaminergic agonist) challenges. Shortened REM latency (less than 50 min during at least 1 night) was present in 67% of depressives. However, REM latency presented a clear night to night intra-patient variability that makes it necessary to record at least 3 consecutive nights for the best sensitivity. Non-suppression after dexamethasone was present in 50% of depressives, blunted GH response after clonidine, in 75% and blunted response after apomorphine, in 42%. A total of 92% of patients exhibited at least one abnormal biological parameter (100% of primary and 75% of secondary depressives); 67% of patients exhibited at least two disturbed parameters and these patients constituted the whole primary depressive group (100%). These results show that these 4 potential biological markers of depression are not necessarily distributed in the same population. This suggests the potential usefulness of their concurrent use for improved accuracy of diagnosis.

Initial study of methylclonazepam in generalized anxiety disorder. Evidence for greater power in the cross-over design.

The anxiolytic activity of methylclonazepam was compared to lorazepam and placebo in a double-blind, randomized cross-over study, using a latin square design, in 18 inpatients meeting Research Diagnostic Criteria for Generalized Anxiety Disorders. Patients presented at least 1 year of symptomatology and had a minimum score of 20 on the Hamilton Anxiety Scale, despite chronic anxiolytic pharmacotherapy. Daily dosage was flexible, from three to six tablets of methylclonazepam 1 mg, lorazepam 2.5 mg, or placebo. Clinical evaluation included Hamilton Anxiety Scale, Clinical Global Impression (CGI), a side-effects checklist, completed every 2 days, and the global preference of the patient for one of the treatment periods. Results showed a highly significant superiority of both benzodiazepines over placebo on the Hamilton Scale (P less than 0.000001) and CGI (P less than 0.001), and also a significant superiority of methylclonazepam over lorazepam on the Hamilton Scale (P less than 0.01), CGI-1 (P less than 0.01), and in the number of patient preferences (14 versus 1; P less than 0.001), with no significant differences in side-effects or related to position in the trial. These results support the value of the cross-over design in chronic and severe anxious inpatients for the demonstration of differences in efficacy between anxiolytic pharmacotherapies.

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.

Concurrent use of REM latency, dexamethasone suppression, clonidine, and apomorphine tests as biological markers of endogenous depression: a pilot study.

In a sample of 12 major depressive inpatients, endogenous subtype (8 primary and 4 secondary) defined by Research Diagnostic Criteria, we compared the sensitivity of four potential biological markers: latency of rapid eye movement (REM) sleep (recorded during at least 4 consecutive nights), dexamethasone suppression, and the clonidine and apomorphine tests. Shortened REM latency (less than 50 minutes during at least 1 night) identified 67% of depressives (87% of primary and 25% of secondary); nonsuppression after dexamethasone identified 50% of depressives (62% of primary and 25% of secondary); blunted growth hormone (GH) response after clonidine identified 75% of depressives (100% of primary and 25% of secondary); and blunted GH response after apomorphine identified 42% of depressives (62% of primary and 0% of secondary). Ninety-two percent of patients were correctly identified by at least one biological marker (100% of primary and 75% of secondary depressives). Of 67% of patients positive on at least two biological markers, all were primary depressives (100%). These four biological markers do not necessarily identify the same population, suggesting that their concurrent use may yield the highest level of diagnostic sensitivity.

Methodology required to show clinical differences between benzodiazepines.

Clinical differences exist between the benzodiazepines but demonstration of such differences requires a more specialized methodology than that normally used in comparative trials. It is recommended that double-blind studies should be carried out in hospitalized patients with severe and chronic anxiety, selected according to precise criteria, and that the trials should be designed as crossover rather than as parallel group studies, with randomization of the stages and flexible dosage. A simple graphic method of representing the clinical profile of individual benzodiazepines is described and it is suggested that this could help clinicians adapt their prescribing to each patient's symptoms.

Duration of benzodiazepine clinical activity: lack of direct relationship with plasma half-life. A comparison of single vs divided dosage schedules of prazepam.

The anxiolytic activity and tolerance of two dosage schedules of prazepam, a long plasma half-life benzodiazepine, were compared under double-blind conditions in two groups of 10 inpatients each who met Research Diagnostic Criteria for Generalized Anxiety Disorder and presented chronic and severe symptomatology. Patients received prazepam 40 mg per day on one of two dosage schedules: divided dosage (DD) - 10 mg in the morning and at noon and 20 mg in the evening; or single dosage (SD) - 40 mg in the evening. The 3 weeks of therapy were preceded and followed by 1 week of wash-out for baseline and follow-up assessments, which were performed weekly with the Hamilton Anxiety Scale, Clinical Global Impression, rating of morning drowsiness and evening worsening of symptoms, and patient self-rating of anxiety by means of a visual analogue scale performed both in the morning and in the afternoon. The results showed a clear superiority of the DD over the SD schedule: better anxiolytic efficacy on the Hamilton Anxiety Scale (P less than 0.0005) and on both morning and afternoon visual analogue scales (P less than 0.01 and P less than 0.0002); less morning drowsiness (P less than 0.0001); and steadier anxiolytic effect during the daytime, as globally rated by the investigator (P less than 0.0001) or measured by morning-afternoon differences on the visual analogue scale (P less than 0.005). These results suggest that plasma pharmacokinetics alone may not be sufficient to predict the duration of benzodiazepine anxiolytic activity.

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.

Pilot study of a specific serotonergic antagonist, pirenperone, in the treatment of anxiety disorders.

Pirenperone (R 47465) is the prototype of a new class of psychotropic drugs, selective serotonin 5-HT2 receptor blocking agents. In an open pilot study, the anxiolytic properties of pirenperone were evaluated in a sample of five anxious inpatients who met Research Diagnostic Criteria for current Generalized Anxiety Disorder and who had a score of at least 25 on the Hamilton Anxiety Scale (HAS). Three dosage levels were tested: 15, 30 and 60 mg/a day in 3 divided doses. Each dosage period lasted at least 5 days, at the end of which patients were reassessed by HAS, Clinical Global Impression and a side-effects checklist. Results suggested a modest anxiolytic activity, without a clear dose-response relationship and with good tolerance. Subsequent treatment by lorazepam (7.5 mg/d) seemed to result in more specific improvement.

Interest of 5-hydroxytryptophan (5-HTP) as a neuroendocrine marker in depressive illness. A negative report.

Among 8 primary depressives, 4 schizophrenics, 4 manics and 4 normal controls, 5-hydroxytryptophan (5-HTP), the precursor of serotonin (200 mg p.o.), appears devoid of any stimulating activity on the liberation of growth hormone (GH). So, 5-HTP test can not be useful as a specific neuroendocrine marker of serotoninergic metabolism in depressive patients.

[Factor analysis of the French revision of the AMDP rating scales. Results of an international study of 388 cases]. / Analyse factorielle de la révision française de l'échelle AMDP. Résultats d'une étude internationale de 388 cas.

A total of 388 patients from 10 Belgian and French Centers were evaluated with the 1981 revision of the psychopathological and somatic scales of the AMDP System. Principal components factor analyses indicate that the somatic items contribute little to the structure. A 10-factors solution of the psychopathological items generate the following factors after orthogonal rotation: Obsessions-Phobias, Dramatization, Anxiety, Depression, Retardation, Organicity, Dissociation, Delusions, Mania, Dysphoria. This structure is similar to the analyses of the previous German edition except for Anxiety (due to additional French items) and Dramatization (which replaces the German factor on Hypochondriasis). The correlations between raw factor scores and item scores of the BPRS and of a similar AMDP-derived scale contribute to the validation of the AMDP factors and to the justification of a 13-item AMDP Syndromic Scale.

[Compatibility between AMDP scales and "Research Diagnostic Criteria" (RDC) for the diagnosis of endogenous depression]. / Compatibilité entre échelles AMDP et "Research Diagnostic Criteria" (RDC) dans le diagnostic de dépression endogène.

Research Diagnostic Criteria represent the most widely used system in research in biological psychiatry to select homogenous samples of patients with a defined psychiatric illness. The AMDP system represents the most complete system for documentation and quantification of psychopathology. On the conceptual point of view, it seems possible to use AMDP psychopathological and somatical scales to select patients who meet criteria of "major depressive disorder" of RDC. In fact, equivalents exist for most of the criteria. For an optimal correspondence, only two psychopathological reserve items--in place of little useful items--and two somatical reserve items could easily be included. A preliminary study has enabled to control the sense of this methodology. A more complete study that verifies the compatibility of both approaches and the ability to automatically select endogenous depressives from AMDP scales is ongoing.

[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.