Biomedical subjects
Publications and source records attributed to E Zarifian.
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.
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.
The possible clinical significance of plasma level monitoring of psychotropic drugs in psychotic patients is described. In particular, data obtained with children and 'resistant' psychotic patients are presented. The results in children indicate the existence of a good relationship between side-effects and haloperidol plasma levels as well as between adverse effects and chlorimipramine plasma levels. Furthermore, an age effect on haloperidol clearance could be shown. Relationship between haloperidol and chlorimipramine concentration and effects could be observed for tics and enuresis respectively but not for psychotic reactions. Data in adult patients illustrate on the one hand possible causes of variability in plasma levels of haloperidol and, on the other hand, the fact that poor bioavailability is not the cause of lack of response in 'resistant' schizophrenic patients.
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.
1. The treatment of schizophrenic symptoms has not the same efficacy in acute and chronic phases of the disease and on the various target symptoms of schizophrenia. 2. The ideal antipsychotic drug might have different properties, sometimes contradictory, to be effective both on paranoid and hebephrenic symptoms which seem to be a mirror image of the same disorder. 3. Basic perspectives in the chemotherapy of schizophrenic psychoses must be founded on better methodological considerations in clinical trials, on a better use of antipsychotic drugs with the help of pharmacokinetic data and computerized EEG and also on new neurochemical findings. 4. Recent data on the mode of action of neuroleptics open up new therapeutic classes of drugs. Such are GABA-like drugs and, more recently, beta-blockers.
Plasma levels of haloperidol were monitored in children and teenagers suffering from psychotic episodes and/or abnormal movements (tics and Gilles de la Tourette's syndrome). Steady-state concentrations of haloperidol ranged from 0.7 to 19 ng/ml without any apparent relationship with the administered dose (15--285 micrograms/kg/day) and a 15-fold variability was observed for the same daily dosage. On the contrary, a significant (p < 0.02) relationship was found between the age of the patients and the plasma concentrations to dose ratios, lower values being present in younger patients. Side effects too appeared to be related to plasma levels, with a significant increase (p < 0.01) in incidence for concentrations over 6 ng/ml. In most of the cases suffering from tics and Gilles de la Tourette's syndrome, a positive response was associated with plasma levels of 1--4 ng/ml, while no relationship could be established for the psychotic group. The relevance of monitoring plasma drug levels when prescribing haloperidol in pediatrics is discussed.
Following a summary of the functional organisation of the ascending dopamine systems, the pharmacology of the dopamine synaptic receptors is considered. The stress is placed upon the differences induced by dopamine agonists during short-term and long-term treatment. In this connection, recent ideas on the heterogeneous nature of the dopamine receptors, on their specificity and on their functional role will be discussed. The dopaminergic action of certain antidepressants will be studied by analysing the different types of activity: presynaptic release, direct pre- or post-synaptic agonism. The role of dopaminergic transmission in depression of mood is considered finally on the basis of clinico-biochemical correlations. Finally, dopaminergic activity is linked with the other possible changes in cerebral monoamines by drafting a table of the interactions between the neurotransmitters.
The biochemical exploration in man is limited by ethical and technical factors. Results are contradictory and it is only by the mean of the antidepressants used as pharmacological tools that monoaminergic hypotheses have been made. The specificity of action of these drugs is very different from one substance to another and the post synaptic impact of the antidepressants is more important than it was thought before. Finally the monoaminergic hypothesis is too simple and cannot summarize the biochemical factors in depression.
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.
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The term "désinhibition" has a different meaning for the psychopharmacologist and for the psychiatrist. The action of anti anxiety agents on animal behavior is described with a special interest for the passive and active avoidance tests. The mode of action and the site of action of benzodiazepines is discussed, focussed on the existence of an endogeneous ligand displacing the binding of diazepam. The differences between low and high doses of anti-anxiety agents are stressed in patients and normal volunteers, and the treatment of inhibition by benzodiazepines is also discussed.
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An open clinical study was conducted with carpipramine in 100 hospitalized subjects presenting various mental disorders. The therapeutic results on symptoms were assessed both as a whole and with the help of a rating scale. Doses varied from 50 to 400 mg per day. Carpipramine seems to be particularly efficient on schizophrenias, 66 cases of which were tested. The best results were observed in hebephrenic forms and depressive syndroms during the illness; in these indications, carpipramine exerts a clear psychomotor stimulating activity which is useful in decreasing indifference, apathy and ideomotor slowness. Schizophrenias with paranoid delusions or depersonalization anxiety tend to be somehow aggravated. Carpipramine does not seem to be a true antidepressant despite its desinhibitory properties. The compound proves useful in deficits of the psychomotor tone such as those occuring in psychasthenia or the deficit syndrom which follows withdrawal from opiates. Clinical and biological tolerances seem to be excellent and extrapyramidal side effects are exceptional. Carpipramine may be considered as a strongly desinhibitory neuroleptic agent which bears some resemblance to antidepressants because of its psychoanaleptic effect. The authors raise the question of possible antipsychotic properties in higher doses in relation to pharmacological data and a bipolar, antipsychotic and predominantly desinhibitory, therapeutic action.
The dosage of the whole tryptophan and of the free tryptophan was conducted in 16 normal subjects to establish reference values and in 12 schizophrenic subjects among whom 7 were under treatment and 5 were not. The method of dosage is made by spectrofluorimetry by increasing the native fluorescence of tryptophan. The results give mean values for the free tryptophan and for the ratio of the free tryptophan to the whole tryptophan values that are higher in the schizophrenics than in the normal subjects used as reference, while the whole tryptophan seems to be little modified ; this increase is more noticeable in the schizophrenics under treatment. The limited number of the cases studied does not enable us yet to establish correlations between the increase of the free tryptophan found in some cases and the nature of the schizophrenia, its age and its evolutivity or even the clinical response to the treatment. However, some figures for the free tryptophan being very much higher than the mean value in some schizophrenics, suggest ways of research for understanding the pathogenisis of schizophrenia and the mechanisms of the therapeutic action of the psychotropic drugs.
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The dosage of the free tryptophan and of the total tryptophan is interesting in psychiatric diseases when a possible role of serotonin is suspected: endogenous melancolia, schizophrenia, sleep disorders. The dosage of tryptophan is made by ultracentrifugation and separation then spectrofluorimetry by increasing 15 times the native fluorescence of tryptophan. The data are given for 16 healthy volunteers and 12 schizophrenics treated and not treated. The methodology of sampling is described and must be strictly standardized to get interpretable data.