Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study.

The central benzodiazepine receptor (cBZr) has long been implicated in anxiety disorders on the basis of: (i) the well-known anxiolytic and anxiogenic properties of cBZr agonists and inverse agonists, respectively; (ii) a possibly reduced sensitivity to benzodiazepines in anxious subjects; and (iii) a putative endogenous ligand. Thus, two main hypothesis have been advanced, namely changes in the concentration or properties of the latter, and changes in the GABAA complex conformation, which contains the cBZr. Neither postmortem studies nor appropriate animal models are available to investigate these ideas. We have used positron emission tomography (PET) to measure both the density and affinity of the cBZr in multiple brain regions in unmedicated patients and age- and sex-matched healthy volunteers, and have looked for differences between groups as well as correlations between cBZr parameters and state and trait anxiety scores. We studied 10 unmedicated patients (sex ratio 1 : 1; mean age: 39 years), prospectively recruited using DSM III-R criteria, and 10 age- and gender-matched healthy unmedicated volunteers. Thanks to a PET procedure using two successive administrations of 11C-flumazenil (at high and low specific radioactivity) and previously validated by us, we estimated the Bmax, Kd and bound : free (B/F) ratios in 11 neocortical areas and in the cerebellum. Before and after the PET session, anxiety scores from Spielberger's and Covi's scales were obtained. There was no statistically significant difference in Bmax, Kd or B/F-values between the two groups for any region. Across the two groups, there were only a few marginally significant anxiety-score-PET correlations, suggesting chance findings. This is the first fully quantitative study to report on the relationships between cBZr parameters and anxiety. Using two independent approaches (i.e. group comparison and across-group correlations), we found no evidence for a link between anxiety trait or state and the cBZr in neocortex or cerebellum in this sample. These findings, if confirmed by studies on larger samples, have implications for the pharmacotherapy of anxiety disorders, and will need to be considered when designing new neurobiological models of anxiety.

No association between dopamine D1, D2, and D3 receptor genes and manic-depressive illness.

BACKGROUND: The dopaminergic receptor genes are candidate genes for manic-depressive illness (MDI). To test this putative involvement we used a case-control study on samples from the native population of the northwest part of France. METHODS: Fifty patients for D1 and D2, 61 patients for D3, and 86-223 controls were tested. RESULTS: No significant association was found between allelic frequencies or genotype counts and MDI, even when the data were pooled with those from published studies. CONCLUSIONS: Single mutations of either of the studied receptor genes are not major determinants of MDI.

Risk factors associated with suicide attempt in young French people.

Demographic data, personal and familial characteristics, as well as DSM-III-R-based psychiatric diagnoses were collected in 369 adolescents and young adults aged between 15 and 29 years, referred to an Emergency Department for psychological problems. In total, 60% of them were suicide attempters. Separations before the age of 12 years and depression in the family emerged as the main features distinguishing the suicidal group from the psychiatric control group. Fifty per cent of suicide attempters were repeaters. Fostering during childhood, suicide attempts and depression in the family were found to be risk factors for repeated self-attempts. These results support the view that significant levels of dysfunction, together with increased psychiatric morbidity, especially suicidal behaviour, characterize the families of young self-attempters.

[Prescription of psychotropic drugs; use, misuse and abuse]. / La prescription des médicaments psychotropes: usage, mésusage et abus.

The prescription of psychotropic drugs in France rises questions dealing with public health and medical ethics. Mental disorders are too often turned into target-symptoms for psychotropic drugs minimizing the importance of individual psychism which requires specific help. Prescribed either excessively or insufficiently psychotropic drugs are used mainly in general practice according to questionable criteria. The importance of a good initial training in pharmacology and therapeutics is stressed. A post graduate medical training totally independent is the only warranty of a prescription adapted to patients' needs.

Suicide attempts and job insecurity: a complex association.

OBJECTIVE: Since Durkheim, epidemiological studies have revealed a significant, complex association between unemployment and suicidal behaviour. The aim of this study was to analyse the relationship between parasuicide and job instability, including unemployment, French social measures against unemployment and occasional work. METHOD: Demographic data, personal and familial characteristics were collected in 541 suicide attempters. RESULTS: Seventy-seven per cent were socially active, with 61.5% in regular employment, and 38.5% in precarious employment. The female-to-male ratio approached 2 in the securely employed sample, and fell to 1 for those with poor social and professional integration. Depression, parasuicide, and alcohol abuse were more common in the families of repeaters in secure employment. The impact of the familial psychiatric background was no longer significant in the job insecurity group. Fostering in childhood was a risk factor for repeat suicidal behaviour in the group with job insecurity.

[Prospective study of attempted suicide]. / Enquête prospective sur les tentatives de suicide.

The present study involves a prospective review of all patients who visited the Emergency Psychiatric Service during the period from December, 6, 1993 to June, 5, 1994. A questionnaire was proposed to 1073 subjects (57.2% females; 42.8% males; mean age = 36.6 +/- 0.89). Demographic data, familial and personal characteristics, previous contacts with professional health services, and diagnosis (DSM III-R criteria) were collected. 52% of them were self-attempters, significatively younger (mean age 34.03 +/- 1.14) and more frequently females (61.5%). The parasuicides were more frequent in their families and in their personal past history. The previous contacts with health services (hospitalizations, consultations) were more frequent among patients who were admitted for psychological and/or psychiatric problems. 54% of self-attempters were repeating suicidal patients. There were more depressive disorders, parasuicides and drug/alcohol abuse in their families. A logistic regression analysis (stepwise) revealed the role of these factors in the repetition of parasuicides. This data supports the significance of a better knowledge of the potential significant factors for parasuicide. Preventive measures are necessary.

[Psychological profile of suicide using firearms to the face. Review of the literature. Our experiences at the university hospital center at Caen]. / Profil psychologique des suicidés de la face par arme à feu. Revue de la littérature. Notre expérience au CHU de Caen.

We studied the psychological feature of subjects who attempted suicide with firearms. This retrospective study included 36 cases of "facial suicide" treated at the Caen University Hospital since 1981 and data in the literature. An analysis of the different parameters showed in several cases, that this population is different from the others, particularly hospitalized drug overdose suicide patients. Two notions were particularly remarkable in these patients: history of patients psychiatric disorders were very rare and recurrent suicide attempts.

[Epidemiological study of patients and suicidal patients admitted to a psychiatric emergency department of a general hospital]. / Etude épidémiologique des patients et suicidants admis aux urgences psychiatriques d'un hôpital général.

The present study involves a review of all patients who visited the Emergency Psychiatric Service during the period from December, 6, 1993 to June, 5, 1994. A questionnaire was proposed to 1073 subjects (57.2% females; 42.8% males; mean age = 36.6). Demographic data, familial and personal characteristics, previous contacts with professional health services, and diagnosis (DSM III R criteria) were collected. 52% of them were self-attempters, younger than the general population and more frequently females (61.5%). The parasuicides were more frequent in their families and in their personal past history. The previous contacts with health services (hospitalizations, consultations) were more frequent among patients who were admitted for psychological and/or psychiatric problems. 54% of self-attempters were repeating suicidal patients. There were more depressive disorders, parasuicides and drug/alcohol abuse in their families. A logistic regression analysis (stepwise) revealed the role of these factors in the repetition of parasuicides. This study supports the significance of a better knowledge of the potential significant factors for parasuicide. Preventive measures are necessary.

A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat.

The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans.

Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography.

The central benzodiazepine receptor occupancy by zolpidem in man is unknown. The present study used positron emission tomography (PET) and [11C]flumazenil to assess in five healthy volunteers, central benzodiazepine receptor occupancy in brain regions with high receptor densities 1 h following an acute oral administration of twice the usual hypnotic dose of zolpidem (20 mg). Receptor occupancy was measured in five discrete structures (middle frontal gyrus, middle temporal gyrus, posterior occipital cortex, lateral parietal cortex, and cerebellar cortex) and in a large neocortical area as the fractional change in the [11C]flumazenil bound/free ratio for the interval 15-40 min post-administration of the radiotracer. The free-radioligand concentration was estimated from the pons, a reference structure virtually devoid of central benzodiazepine receptor. With individual pons values, mean occupancy was about 21% but with spurious inter-subject variability. With pons values averaged across the five subjects and separately for control and treated condition, the occupancy was (mean +/- S.D.) 27 +/- 11% for the whole neocortex, and ranged from 26 to 29% in the five discrete structures (P < 0.01). By showing hypnotic effect at moderate occupancies, this study directly provides evidence for the full-agonist properties of zolpidem in human.

Topographic EEG activations during timbre and pitch discrimination tasks using musical sounds.

Successive auditory stimulation sequences were presented binaurally to 18 young normal volunteers. Five conditions were investigated: two reference tasks, assumed to involve passive listening to couples of musical sounds, and three discrimination tasks, one dealing with pitch, and two with timbre (either with or without the attack). A symmetrical montage of 16 EEG channels was recorded for each subject across the different conditions. Two quantitative parameters of EEG activity were compared among the different sequences within five distinct frequency bands. As compared to a rest (no stimulation) condition, both passive listening conditions led to changes in primary auditory cortex areas. Both discrimination tasks for pitch and timbre led to right hemisphere EEG changes, organized in two poles: an anterior one and a posterior one. After discussing the electrophysiological aspects of this work, these results are interpreted in terms of a network including the right temporal neocortex and the right frontal lobe to maintain the acoustical information in an auditory working memory necessary to carry out the discrimination task.

[Clinical trials and good clinical practices. Results of a telephone survey in Basse-Normandie among 867 physicians]. / Essais cliniques et bonnes pratiques cliniques. Résultats d'une enquête téléphonique réalisée en Basse-Normandie auprès de 867 médecins.

In order to evaluate what doctors think about clinical trials in general, 867 of them practicing in western Normandy were polled by telephone. The majority of the doctors questioned (68.6%) said they were interested in participating in clinical trials. Moreover, a number of them (71.7%) had already taken part in such studies, most of which were non-comparative studies on drugs already on the market. 66.2% of the doctors said they were willing to participate in such trials but only 10% of the doctors questioned knew anything about Good Clinical Practice. Doctors practicing in this part of France appear to know little or nothing about Good Clinical Practice, however, while they are willing to take part in clinical research, they are insistant that trials should be of worthwhile interest.

[Hemispheric functional specialization and anxiety. Focus on an evaluation procedure]. / Spécialisation fonctionnelle hémisphérique et anxiété. Mise au point d'une procédure d'évaluation.

Observations of brain-lesioned patients and experimental psychology studies have shown that the influence of the specific functioning of the two hemispheres of the brain on the regulation of emotional behaviour appears to be unequal and suggests a functional specialization of the right hemisphere for the expression and comprehension of the affective components of behaviour. However, the extension of this hypothesis to include all emotional experiences remains controversial. The observed superiority of the left hemisphere in the perception of positive emotions and the predominance of the right hemisphere in the treatment of negative emotions would appear to favour a joint and complementary participation of both cerebral hemispheres in emotional experiences. In the case of affective disorders, and particularly in anxiety symptoms, the hypothesis of a dysfunctioning of the right hemisphere is similarly questioned: while all metabolic studies corroborate this hypothesis, experimental psychological studies suggest the existence of a preferential involvement of one or the other hemisphere in relation to individual differences such as the "trait" anxiety score. Moreover, the few studies which have been undertaken with healthy volunteers raise the problem of their extrapolation to pathological situations. In view of the potential interest in the neuropsychological evaluations of subjects with different forms of pathological anxiety, we have developed an experimented with two tests aimed at evaluating the differential activity of the two hemispheres of the brain. These two tests, constructed on a "mirror-image" model from the specifications of a functional hemispheric specialization, are supposed to involve cognitive strategies pinpointing preferentially one hemisphere or the other.(ABSTRACT TRUNCATED AT 250 WORDS)

[Recent progresses in the biology of schizophrenia]. / Progrès récents dans la biologie de la schizophrénie.

Investigations designed to improve our understanding of the physiopathology of schizophrenia are progressing along various, but no necessarily exclusive, lines. The most important aspects of the recently established biological data and their potential value are discussed and compared to classical hypotheses and results.

Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography.

Studies of central benzodiazepine receptors in the human brain in vivo are now possible using positron emission tomography (PET) and [11C]flumazenil. With the aim of measuring Bmax and Kd in brain regions, we used a two-injection [11C]flumazenil (at high and low specific radioactivity, respectively) pseudo-equilibrium paradigm to evaluate, in seven unmedicated healthy volunteers, the relative merits of three 'reference' structures (pons, hemispheric white matter and corpus callosum) in which the free radioligand concentration in brain tissue was estimated 15-40 min after i.v. injection of the radioligand. By means of high-resolution PET, the Bmax and Kd were calculated for each subject in 18 gray matter structures, based on a two-point Scatchard plot. We found that the use of the corpus callosum as reference often resulted in spurious Bmax and Kd values. The pons was the best reference structure because it provided satisfactory Bmax values (closest to in vitro data) and most consistent Kd values, and was the region easiest to sample on PET images. The pattern of regional Bmax was consistent with that expected from in vitro studies, with values highest in the cerebral cortex, intermediate in the cerebellum, and lowest in the striatum and the thalamus. The Kd values were uniform among regions and were consistent with earlier in vitro and in vivo data. This work documents the feasibility of estimating Bmax and Kd of central benzodiazepine receptors in multiple brain regions for clinical research.

[Panic disorder and microcirculation. Controlled study of capillaries in anxiety disorders]. / Trouble panique et microcirculation. Etude contrôlée des capillaires sanguins dans les troubles anxieux.

However varied the clinical descriptions of anxiety, a sizeable proportion is always allotted to the cardiovascular aspect. One is reminded of Krishaber's cerebral-cardiac neuropathy and Brissaud's conception of anxiety. The implication of the heart in anxiety disorders, especially paroxystic disorder, i.e. panic attacks (PA) is important. Cardiovascular symptoms (tachycardia, increased systolic blood pressure, chest pain) are among the most frequent manifestations of panic; furthermore, recent studies suggest that male panic disorder (PD) patients have an increased mortality risk from cardiovascular diseases. It is with this implication in mind that we undertook this study, the main aim of which was to confirm the existence of an abnormal microcirculation, characteristic of PD, taking the form of an excess number of twisted capillaries. Abnormal capillaries had been described previously in non-controlled studies of patients with psychiatric disorders diagnosed as neurasthenia, neurosis, neurovegetative disorders and more recently as neurocirculatory asthenia, a syndrome similar to PD. This led us to undertake a study of the total number of capillaries observed by photomicrography (capillaroscopy) in the supra-ungueal fold of the fingers of both hands (except thumbs), comparing the number of twisted capillaries of 16 subjects suffering from panic disorder with or without agoraphobia according to the DSM III-R criteria, with those of 16 healthy volunteers matched for age and sex and 14 subjects suffering from other anxiety disorders (10 of them fulfilling criteria for generalized anxiety disorders).(ABSTRACT TRUNCATED AT 250 WORDS)

[Benzodiazepines in the treatment of anxiety]. / Benzodiazépines dans le traitement de l'anxiété.

During the last ten years, the treatment of anxiety disorders has changed considerably. Cognitive-behavioural therapies and new chemotherapies have been added to benzodiazepine therapy and psychotherapy which for a long time had been the only treatment of these frequent and invalidating disorders. Recent reports of possible drawbacks in prolonged benzodiazepine therapy provide another reason to reconsider the indications of these drugs now that other drugs are available. Benzodiazepines remain the treatment of choice for recent anxiety states requiring some degree of sedation and rapid relief, but their long-term administration should be reserved to patients who did not respond to other treatments. The authors propose several guidelines for a better prescription of these anxiolytic agents and for more rational indications taking into account the advantages of other available treatments.

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies.

Flumazenil is a specific antagonist of the central benzodiazepine receptor (CBZR). Labelled with 11C, this compound is the reference radioligand for positron emission tomography (PET) study of the CBZR in humans and primates. The time-course of [11C]-flumazenil radioactivity and its main acid metabolite [11C] Ro 15-3890 were reconstructed from the time-course of total radioactivity in plasma after administration with high or low SRA in primates and humans, applying an extraction procedure validated by TLC. The measured pharmacokinetics of [11C]-flumazenil (T1/2 beta = 45.1 +/- 12.3 min, T1/2 alpha = 1.5 +/- 1.5 min; K = 0.14 +/- 0.14 min-1; Vd area = 44.0 +/- 17.0 l; Clp = 40.0 +/- 8.5 l/h) exhibited a very rapid distribution phase followed by fast elimination, with a large volume of distribution; these results were confirmed by HPLC determinations and agree with previously published data on unlabelled flumazenil. Pharmacokinetics of [11C] Ro 15-3890 acid metabolite show that high drug concentrations in the blood are promptly achieved (kf = 0.13 +/- 0.004 min-1), with a very rapid elimination half-life (T1/2m = 4.47 +/- 1.31 min) comparable to that of [11C]-flumazenil. The percentage metabolization of parent compound to the acid [11C] Ro 15-3890 was constant from the 15th minute and was significantly higher in man compared to the monkey. This percentage was increased by prior eating. The other putative metabolites, i.e. labelled [11C] Ro 15-4965 and unlabelled Ro 15-5528, were never observed at detectable concentrations with TLC and HPLC in rabbit, baboon and human blood samples. This pharmacokinetic study of plasma flumazenil may be useful to implement a dynamic method of CBZR quantification using PET and for analysis of pharmacokinetics in brain tissue.

EEG cartography before and after visual stimulation: a group study with descriptive non-parametric analysis of EEG data.

Ten right-handed students were submitted to a protocol of cognitive visual stimulations based on six successive sequences: EC1, EO, B1, B2, B3, EC2. Following a first "eyes closed" (EC1) multiple EEG recording (16 EEG leads, plus polygraphy), and an "eyes-open" recording (EO) with central visual fixation, 60 computer-controlled slides were presented successively for each of three successive recordings (B1, B2, B3) before the last "eyes-closed" recording (EC2). In B1, the subjects were asked to look at the meaningful black and white drawings presented without comment. In B2, a second set of similar pictures was presented, with the advice to try to remember later on the visually projected slides. In B3, a memory recognition task was introduced with 20 slides coming from the B1 set, 20 from the B2 set, completed by 20 new slides. Each slide was presented for 10.24s. followed by a beep audio-signal indicating that the subjects should press electronic mouse knobs alternatively in B1, B2, and for indicating their answers in B3. After artifact rejection, EEG spectral analysis was followed by parametrization and group studies applying Fisher non-parametric paired exact probability tests. Nine comparisons were computed: EC1-EC2, EC1-EO, EC2-EO, EO-B1, EO-B2, EO-B3, B1-B2, B1-B3, B2-B3. A statistical strategy of descriptive inter-individual non-parametric. Fisher tests was undertaken, together with computation and mapping of averaged spectral parameter differences (mean amplitudes and frequencies, mean amplitudes %, resonance coefficients) for raw EEG, delta, theta, alpha, alpha 1, alpha 2, beta 1 and beta 2 frequency bands and probability maps.(ABSTRACT TRUNCATED AT 250 WORDS)