Impact of neuroleptic chemotherapies on schizophrenic psychoses.

The author reviews the impact of neuroleptic chemotherapy on various forms of schizophrenia in the 25 years since the introduction of chlorpromazine in psychiatry. The activities of the different types of compounds are related to the symptomatic and progressive forms of the psychosis, with an emphasis on the "dual structure" of the illness. Problems of drug efficacy, the need for new drug treatments, and methodological issues in research in these areas are discussed.

Dopaminergic receptor sites in human brain: positron emission tomography.

Positron emission tomography (PET) and 11C-labeled pimozide were used to study the dopaminergic (DA) receptor sites in the human striatum by comparing the latter with the cerebellum, which lacks DA receptors. Although 11C-pimozide concentration was not different in these two brain structures up to 53 minutes after IV injection (thus implying large nonspecific binding), a significant retention of radioactivity in striatum relative to cerebellum was found in controls but not in subjects pretreated with the unlabeled competitor haloperidol. This suggests that the striatal retention seen in controls was due to specific binding of 11C-pimozide to DA receptor sites, whereas prior occupation of the receptor sites by the unlabeled competitor was achieved in pretreated subjects.

Parenteral loxapine in severely disturbed schizophrenic patients.

Loxapine is a tricyclic antipsychotic drug of the dibenzoxapine class. An uncontrolled open trial of this compound has been performed by intramuscular route in 28 patients previously refractory to other neuroleptic drugs. These patients received 50 to 200 mg loxapine daily by intramuscular route. Clinical evaluation, BPRS, NOISE and biological evaluation were performed before and at the 8th day of the treatment. Global clinical evaluation and statistical analysis of BPRS showed the high efficacy of loxapine with a sedative effect during the initial phase and a disinhibiting and "hallucinolytic" character at a later stage. Tolerance to the preparation appeared good both locally and systematically with the possible exception of transient effects upon body temperature.

Position of tianeptine among antidepressive chemotherapies.

The advent of a new antidepressant is always received with both interest and scepticism by clinicians. No new compound has yet been shown to be more efficient than imipramine in the treatment of depression. In determining the position of a compound among the antidepressants, four levels are to be considered: (a) Chemical family: Tianeptine is a tricyclic compound of dibenzothiazepine type. It is the only representative of this subgroup. (b) Biochemical activities: Tianeptine increases the presynaptic uptake of serotonin after single as well as repeated administration; but this action is not linked to any effect on the 5-HT post-synaptic systems. Electrophysiological modifications are observed in the locus coeruleus (noradrenergic) at 2.5 times higher doses; nevertheless, the essential action involves the serotoninergic systems. Tianeptine has no affinity for alpha 1 adrenergic and H1 antihistaminic receptors; this affinity is responsible in a large part for the sedative anxiolytic properties of antidepressants. Tianeptine has no affinity for the muscarinic receptors. It has secured its place among the non-anticholinergic antidepressants. The mechanism of action or the therapeutic profile cannot be inferred from this original biochemical profile. (c) In clinical trials, the double-blind trials confirm the antidepressant efficacy in essentially neurotic depressive syndromes, similar to that of imipramine, nomifensine, amitriptyline. They do not show a shorter onset time of antidepressant activity. The therapeutic profile appears to be neither stimulating nor sedative. Some arguments are in favor of an anxiolytic activity. Others favor a more psychotonic profile. Tianeptine can be classified among the mid-position antidepressants. (d) With respect to clinical acceptability, tianeptine has no anticholinergic effect and no cardiovascular effect.

Brain distribution and kinetics of 11C-chlorpromazine in schizophrenics: positron emission tomography studies.

The positron emitter 11C (20 minutes half-life) permits the labeling of chlorpromazine (CPZ) and the study of its distribution in humans by external counting. Trace amounts of 11C-CPZ were injected intravenously into 22 schizophrenic patients all untreated for several months with neuroleptics. The brain uptake was 6.04 +/- 1.6% of the injected dose 15 minutes after the injection, and it remained constant for 45 minutes. By positron emission tomography, the drug distribution was shown to be in the gray matter, and such structures as the cortex, caudate nucleus, thalamus and putamen could be identified. This new methodology will be helpful in studying specific receptors in humans in a noninvasive way.

[Caffeine and EEG mapping: effects of visuo-spatial task in healthy volunteers]. / Caféine et cartographie EEG: effets d'une tache visuospatiale chez des volontaires sains. Stratégie d'analyse des données électropharmacologiques.

A group of 10 subjects, normal volunteers (6 men, 4 women), mean age 27.2 years, right-handers, has been selected for a double-blind study of caffeine effects (400 mg per os) versus placebo. One week delay separated the two EEG sessions quantified by spectral analysis. During each session (16 EEG channels, common reference), each subject was recorded four times: 2.5 min, in eyes-closed condition, under diffuse attention, followed by 2.5 min, during a visuo-spatial task ("eyes open" condition: presentation of a picture). These two EEG recordings were obtained before the oral administration and repeated 1 hr after the administration of caffeine or placebo. Individual and group results presented globally: 1) an increase in mean frequencies of alpha activity in "eyes closed" condition, and of delta activity in "eyes open" condition; 2) a decrease of alpha activity amplitudes (both RMS and % values) in both conditions; 3) a decrease of total RMS amplitudes in "eyes closed" condition; 4) an increase of relative % amplitudes for beta 2% fast activity in the "eyes open condition". These results characterize the psycho-stimulant effects of caffeine, especially over the left temporal area which was confirming an initial statistical hypothesis of specific cerebral local activation. The non-parametric permutation tests of Fisher, were not always reaching statistical significance for the same EEG channel quantified by one of the 17 analyzed spectral parameters, except on the left temporal area. During the visuo-spatial task, the decrease in alpha amplitudes (RMS and %) was also statistically significant, but over larger areas: over left and right temporal, central and parietal regions. In both conditions, eyes closed and eyes open, the alpha RMS amplitude was also decreased over the right anterior frontal area.

[In vivo study of central serotoninergic receptors in man using positron tomography]. / Etude in vivo des récepteurs sérotoninergiques centraux chez l'homme par tomographie à positons.

In an attempt to characterize in vivo the central serotonergic (5-HT2) receptors in humans with positron emission tomography (PET), we have used 11C-labeled-ketanserin, a seratonergic antagonist that has high affinity and selectivity for the 5-HT2 receptors in vitro. Earlier in vivo studies in rats had demonstrated a preferential accumulation of 3H-ketanserin in the frontal cortex relative to cerebellum, in accordance with known differences in density of 5-HT2 receptor in these two brain structures (5-HT2 receptors are dense in frontal cortex and sparse or absent in cerebellum). In rats, tracer accumulation in frontal cortex represented specific binding of 3H-ketanserin to 5-HT2 receptors in vivo as demonstrated by inhibition, saturation, and displacement studies. In 5 control subjects, we found a statistically significant retention of 11C-ketanserin in frontal cortex relative to cerebellum after intravenous injection of a tracer dose of the radioligand, suggesting specific in vivo binding of 11C-ketanserin to frontal cortex. To substantiate this hypothesis, we studied 4 subjects administered unlabeled chlorpromazine (CPZ) intramuscularly in therapeutic amounts (75 mg) two hours before the PET study. Pretreatment with CPZ decreased significantly the retention of 11C-ketanserin by the frontal cortex, indicating that almost total occupation of the ketanserin receptors by CPZ had been achieved prior to the injection of the radioligand. Despite these positive results, both the duration and the magnitude of tracer retention by frontal cortex in control subjects were much smaller than was reported in rats, presumably indicating lower specific binding, higher nonspecific binding, and faster drug metabolism in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

[The value of the measurement of intra-erythrocytic lithium in the bio-clinical surveillance of lithium therapy (author's transl)]. / Intérêt du dosage du lithium intra-érythrocytaire dans la surveillance bioclinique de la lithiothérapie.

THe correlation between red cell lithium concentration and signs of neurotoxicity have been reported in the literature by a great majority of authors. A deficiency in the lithium-sodium counter-transport mechanism may be responsible. Measurement of blood lithium levels only is not always sufficient to identify in the laboratory patients showing signs of intolerance. The three cases reported here indicate the limitations of the measurement of plasma lithium levels and the perfect correlation between neurological signs and erythrocyte levels. In vitro studies of transmembrane ion exchanges should make it possible to undertake an investigation before starting treatment in order to identify the risks of cellular toxicity.

[Present nosology of the affective disorders (author's transl)]. / Nosologie moderne des troubles de l'humeur.

The present nosology of the affective disorders seems accurate enough to enable valid definitions and classifications to be made, despite the differences between the countries and the methods of approach. Nevertheless, there has been much controversy regarding different clinical types, similar or opposite, and notably about whether the pathogenesis and etiology are single multiple. Consideration must be given not only to the clinical form presenting but also to the course (episodic, recurrent or chronic) and to the circadian variations. Moreover, it is absolutely essential to distinguish in the nosology, on the one hand, the clinical picture proper and, on the other hand, the aetiology or the psychic structure. Thus, a simple depression may be related to an endogenous process and a melancholic state may be reactive. The theoretical problems of classification may justify the use of multivariate analysis. However, it is doubtful whether sophisticated methods are absolutely necessary in clinical practice.

[A scale to assess psychasthenia]. / Une échelle pour évaluer la psychasthénie.

"Psychasthenia exists--we meet it every day". Despite this affirmation, Pierre Janet's views remain unappreciated by international psychiatry. Psychasthenia is not included in the Diagnostic and Statistical Manual of Mental Disorders (DSM III-R). This pathology, described by Janet as both benign and terrible, is presently broken into many diagnostic categories with respect to the principal symptomatology of the patient. When a mood disorder is present, these patients can have diagnostic criteria for major depression or dysthymia. Patients with prevalent anxiety, phobia or obsessive-compulsive symptoms, must also be classified in having anxiety disorders. When somatic complaints are major symptoms, the patient's disease can be, on the whole, attributed to a somatoform disorder. This scale is a global evaluation of psychasthenia. It is made up of three lists of items. The first concerns asthenia or fatigue sine materia. The items in this group allow an evaluation of the physical and mental characteristics of asthenia associated with an inability of acting. Difficulties in mental concentration are measured by items in the second list. Mental processes are associated with doubts and waverings. They are interrupted by interferences caused by obsessions with recurrent and persistent ideas, impulses or images. Physical symptoms without organic pathology or a pathophysiologic mechanism constitute the neurasthenic part of psychasthenia. In the third list, somatic complaints are spelled out in a check-list of these potential symptoms. This scale can be used as a help in the diagnosis. Items 2, 3, 5, 25, 26 and 29 have a specific reference to the history of the disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical effects of long-term lithium treatment on sleep, appetite and sexuality]. / Effets cliniques des traitements prolongés par les sels de lithium sur le sommeil, l'appétit et la sexualité.

The authors try to determine the incidence of long-term lithium treatments on sleep, appetite and sexual behaviour. The study was conducted in fifty outpatients of both sexes who have been for at least six months on lithium only and whose mood disturbances are stabilized. In two thirds of the cases of this clinical study, lithium seems to have beneficient qualitative and quantitative effects on sleep as opposed to other psychotropic drugs which cause discomforting sleepiness. Lithium seems to influence appetite slightly although it is responsible for the gain in weight in a fourth of the treated outpatients. Half of the subjects consider that lithium modifies their sexuality towards a decrease of the desire without modifying their capacities of realization. In a comparison study conducted with the psychotropic drugs that had been administered before, the repercussions of lithium on sexuality appear thus opposite to those of psychotropic drugs, major tranquilizers and antidepressants which impair the capacities without reducing the desire. Despite the specific side effects on some instinctive functions, lithium seems to be a treatment well lived by the subjects.

[The place of carpipramine among the psychotropic agents]. / Place de la carpipramine parmi les psychotropes.

Our purpose is to find objective statistic tests for classification of all psychotropic drugs. First a multifactorial analysis determine six profiles of groups. Results objectively confirm Delay and Deniker's classification and point out intermediate position of carpipramine. A specific method tries to put Carpipramine in one of these groups i.e. discriminant analysis. By this method it is impossible to classify nineteen psychotropic drugs, Carpipramine being one of them. Its clinical properties cannot brin together Carpipramine and other psychotropic drugs.

[Efficacy of tianeptine in the treatment of psychasthenia. A study versus placebo]. / Efficacité de la tianeptine dans le traitement de la psychasthénie. Etude versus placebo.

Tianeptine is an effective antidepressant with original neurochemical properties. Tianeptine increases the serotonin (5-HT) reuptake after acute and chronic treatment. The efficacy of tianeptine (T) versus placebo (P) was evaluated in the treatment of psychasthenia, because of the role of 5-HT in obsessive-compulsive disorders, the last state of psychasthenia in term of severity. Patients were recruited using the psychasthenia scale; then, their MADRS scores limited those who turned out to the depression. Mean inclusion MADRS scores where 12 (T) and 11.8 (P). Tianeptine is an effective treatment for patients suffering from psychasthenia. Tianeptine is more effective than placebo in global score and in sub-scores (asthenia and somatic symptoms) of the psychasthenia scale. In spite of weak inclusion scores in MADRS, patients taking tianeptine also showed significant improvement, greater than with placebo. The percentage of patients with a reduction equal to or greater than 50% of their MADRS score was significantly more important in tianeptine group. These results could be the illustration of the decrease in associated depressive symptoms or the result of an improvement of symptoms common to MADRS and psychasthenia scales. The same favorable results were obtained in symptoms of anxiety scored by HARS. In term of safety, tianeptine is equivalent to a placebo if we consider somatic complaints expressed by the patients, global improvement evaluated by the patient and the investigator, weight and blood pressure. Interruption of treatment for side-effects concerns the placebo group only (3 versus 0). This excellent safety is particularly well-adapted to the treatment of these out-patients.

[Psychotropic drugs and mechanisms of mood regulation]. / Médicaments psychotropes et mécanismes de régulation de l'humeur

Pharmaco-psychiatry has contributed to the study of mood regulation mechanisms (thymo-regulation). Anti-manic neuroleptics may induce depressions: anti-depressants may cause mood inversion (with artificial "bipolarity"), and lithium has an action upon alternating disorders of the mood. Correlations with the extrapyramidal syndromes are to be noted: parkinsonism going along with depression, and the antiparkinsonian action with the stimulation of mood. The extent of the role played by neuro-hormones, beta-inhibitors, and releasing-factors is still under discussion. The theoretical notion of mood regualtion makes it possible to single out a special type of psycho-stimulation implying manifold applications.

[Prolonged-action drugs in psychiatric therapeutics : gaps and needs]. / Les médicaments d'action prolongée en thérapeutique psychiatrique : lacunes et besoins

The most accomplished model in this type of therapy is presently that of the long-acting neuroleptic (L.A.N.). Some target-symptoms are privileged : schizophrenic inertia (piportil or flupentixol derivatives), delusions (fluphenazine derivatives). But on the other hand, a sedative action has not been considered as benefic in long-acting drugs, and we're still in need of an L.A.N. whose hallucinolytic action would favourably compared with haloperidol. In the field of antidepressants, improvements appear as necessary. It is highly desirable to find compounds whose action would be really powerful, whose duration of action would last more than 24 or 48 hours ; the compound being administred either as an embonate or intra-muscularly in an attempt to limit the risks of suicide. Researches are being conducted : 1) to obtain long-acting antiparkinsonian correctors ; 2) to find out some form of lithium salts which, after one administration, would allow a stable nycthemeral lithiemy.

[Tardive dyskinesia induced by neuroleptics. A review of the literature]. / Les dyskinésies tardives des neuroleptiques. Revue de la littérature.

Neuroleptics can induce not only early but also tardive extrapyramidal side effects. The former were described as early as in the beginning of the therapeutic era; the latter, known as tardive dyskinesia, are essentially made of bucco-linguomasticatory dyskinesia, sometimes accompanied by other extrapyramidal symptoms, among others choreo-athetoid movements of the limbs. This complication was most often reported in elderly people, when a long-lasting neuroleptic treatment is withdrawn; but it can also appear in young people and after a neuroleptic treatment of only a few weeks duration. The trouble occurs or is worsened when neuroleptics are withdrawn and is reduced when dosage is increased; it responds to the theoretical model of denervation supersensitivity. Symptoms may be reduced by blocking the dopaminergic receptor, or by reducing dopaminergic transmission, or, may be, by increasing cholinergic activity. Now, treatment is first and foremost prevention.

[A French experience with methadone]. / A propos d'une expérience francaise de la méthadone

Methadone chlorhydrate has been administred to opiate addicts either for a short period with a decreasing dosage as a withdrawal cure, or for longterm treatments as a basis of a maintenance program. The analysis of precise clinical criteria regarding the socio-professional states, the family-life, the general health and the psychopathological diagnosis, allows an evaluation of the success of the cure and of its elective indications. The study of the personnality of the drug-addicts shows the importance of this factor in the potential success of a methadone cure. Urinary biological controls are regularly performed. This limitations and promises of this treatment discussed form a basis of a year's experience.

[Value of pharmacokinetic data during the treatment of psychoses with haloperidol]. / Intérêt des données pharmacocinétiques au cours des traitements des psychoses par l'halopéridol.

Pharmacokinetic data of psychotropic drugs should allow a better understanding of therapeutic results and side effects. The different factors influencing liberation, absorption, protein binding, distribution, metabolism and excretion are reviewed. Then, the principal pharmacokinetic data of haloperidol are exposed with a special emphasis on the lack of information about the correlations between plasma levels and clinical effects. The role of pharmacokinetic informations in the interpretation of responses to treatment is detailed, wishing that the monitoring of haloperidol plasma levels will be more developped in a next future.

[Loxapine succinate: a new neuroleptic]. / Le succinate de loxapine: un nouveau neuroleptique.

Commercialized in the U.S.A. a few years ago, the loxapine succinate appears to be interesting among neuroleptic compounds. Used in 28 chronic schizophrenics, 19 of which were neuroleptic resistent patients, the parenteral route proved to be anti-psychotic and sedative in 26 patients. The usual daily dosages were between 100 and 200 mg. The local and general tolerances were good. The side effects were mild and essentially vegetative. The therapeutic efficiency seems to be better at the same dosages with the oral form than with the parenteral form.

[Treatment with tianeptine of depressive disorders in drug addicts under withdrawal. Assessment of efficacy and study of dependence]. / Traitement par la tianeptine des syndromes dépressifs des toxicomanes sevrés. Appréciation de l'efficacité et recherche de dépendance.

The study concerns the use of a new antidepressant, tianeptine, as a treatment of depressive and/or amotival syndrome, in 30 drug addicts, detoxified from opiates. From a thymoanaleptic point of view, 85% of the patients exhibit a positive result after 28 days of treatment with 37.5 mg/day. These good results are confirmed by the evolution of the Hamilton Depression Rating Scale global score, which significantly decreases from D0 to D14 and from D14 to D28. The acceptability of the antidepressant is good. Anticholinergic side-effects are very uncommon. Tianeptine appears devoid of any obvious psychostimulant or sedative effect. The drug compliance, estimated by counting the tablets, is very satisfying: there is no tendency to a spontaneous increase of dosing. The follow-up of the patients after drug cessation has not shown any symptoms suggesting psychological or physical dependence towards the drug. During this study in subjects particularly predisposed to the abuse of psychoactive drugs, tianeptine has not induced anything suggesting the possibility of drug abuse or tolerance.