The differential therapeutic outcome in schizophrenia of compounds acting at D2-receptors.
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Benzamides↗
Biomedical subjects
M Ackenheil
Publications and source records attributed to M Ackenheil.
Cellular immunity in schizophrenic patients before and during neuroleptic treatment.
A possible connection between immunological alterations and schizophrenia has been discussed for many years. We studied 55 schizophrenic patients in an acute stage of illness before they began neuroleptic treatment. 35 patients who showed clinical improvement on neuroleptics, and 51 healthy controls. Our interest was focused on parameters of cellular immunity. We found an increased lymphocyte response to stimulation with pokeweed mitogen (PWM) and phytohemagglutinin (PHA) in patients before neuroleptic therapy and also an increased response to stimulation with PWM and PHA during treatment compared to controls. Stimulation with antigens generally showed a lower lymphocyte response in patients than in controls, but the difference was only significant after stimulation with tuberculin before neuroleptic treatment and after stimulation with varidase, diphteria-toxoid, tuberculin, vaccinia, and rubella during neuroleptic treatment. The number of CD3+ and CD4+ cells, but not the number of CD8+ cells, was increased before and during treatment in comparison to controls. Suppressor-cell activity was reduced in three different suppressor cell assays before and during neuroleptic medication compared to controls. We therefore conclude that alterations of the immunological system which are, as has been demonstrated, not due to treatment with neuroleptics might play a role in schizophrenia.
Adolescent↗
[The biochemical effect profile of zotepine in comparison with other neuroleptics].
The clinical action of a neuroleptic depends on its biochemical and pharmacological profile which is related to pharmacokinetic and pharmacodynamic properties. All neuroleptics influence not only the various dopaminergic systems but also more or less markedly the alpha-adrenergic, acetylcholine, histamin, serotonin and GABA systems. In this regard we can describe zotepine (a tricyclic neuroleptic from the group of the dibenzothiepines, with a central seven-membered ring) as follows: It is to some extent comparable with chlorpromazin in respect of its antidopaminergic activity, but zotepine exercises a more marked blocking action on the D1 receptors than the classical neuroleptics. 5-HT1 and 5-HT2 receptors are also among the receptors that are most markedly blocked by zotepine. The action on the noradrenergic system is more pronounced than that of chlorpromazin, thioridazin or haloperidol. It exercises a merely medium-grade action on the cholinergic system. This receptor blocking profile could explain the rare occurrence or the mild manifestation of extrapyramidal motor disturbances in the clinical use of zotepine.
Animals↗
[Effectiveness and tolerance of zotepine in a double-blind comparison with perazine in schizophrenic patients].
40 inpatients suffering from a schizophrenia (ICD-9) were treated with either zotepine or perazin. The study was continued for a period of 28 days. Assessment of clinical efficacy was effected via BPRS, AMDP, CGI and SANS; tolerance was assessed by means of Simpson's scale. In addition, EEG, ECG and laboratory controls were conducted. The overall therapeutic efficacy was good, and it was not possible to distinguish one group from the other, i.e. both substances were equally effective, judged by means of the psychopathometric tools that were at our disposal. In 11 patients of the zotepine group and in 9 patients of the perazin group, slight extrapyramidal symptoms were observed. No clinically relevant changes were seen in EEG, ECG and laboratory controls in both groups.
Adult↗
[Clinical effectiveness of zotepine in treatment of negative schizophrenic symptoms. Results of an open and a double-blind controlled trial].
The clinical action of Zotepine was examined in an open and in a randomised double-blind controlled study in in-patients displaying a productive or minus pattern of symptoms within the framework of a schizophrenic disease or schizoaffective psychosis. The present paper discusses only the results achieved in treating schizophrenic minus patterns of signs and symptoms. In Study I 20 schizophrenic patients were treated with two different Zotepine dosages. Group 2 (n = 12) showed at an average daily dose of 168 +/- 15 mg (150-190 mg) a significant improvement (p less than 0.05) of the anergy subscore in the BPRS scale as well as a significant improvement of the subscores affective flattening, anhedonia/asociality and attentional imparvement in the SANS scale, compared with Group 1 (n = 8) with an average daily dose of 270 +/- 37 mg (240-340 mg). This improvement developed already during the first two weeks of the treatment. In Study II the antipsychotic action of Zotepine compared to that of perazine was studied under double-blind conditions. The average daily dose in the Zotepine group (n = 20) was around 241 +/- 70 mg (106-396 mg), in the perazin group (n = 19) at 348 +/- 09 mg (214-575 mg). With regard to the BPRS subscore anergy and all the subscores of the SANS scale, there was a distinct improvement without significant group differences. Both substances were comparably well tolerated.
Adult↗
High affinity 3H-spiperone binding to lymphocytes: reality of artefact?
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Humans↗
Coincidence of schizophrenia and hyperbilirubinemia.
In a retrospective study, the bilirubin plasma concentrations of every patient admitted to the Psychiatric Hospital were collected. Patients suffering from liver disease, substance abuse, overt hemolysis, or increased liver enzymes were excluded. Schizophrenics showed a significantly higher incidence of hyperbilirubinemia than patients suffering from other psychiatric disorders. This phenomenon seems to be independent of drug usage and therefore points to a relationship between hyperbilirubinemia and schizophrenic psychosis. Hypothetic explanations, such as a possible genetic disposition for Gilbert Syndrome, an increased vulnerability of red-cell membranes, and the role of estrogens in schizophrenic patients, are discussed.
Adult↗
The mechanism of action of antidepressants revised.
The discovery of the clinical efficacy of imipramine and of the MAO-inhibitor iproniazid intensively stimulated biochemical-pharmacological research on the mechanism of action of antidepressants. Due to these investigations, until recently an enhanced activity of the central noradrenergic and/or serotonergic transmitter system was considered essential for the clinical antidepressive action. Such enhancement could be achieved either presynaptically by blocking alpha 2-adrenergic receptors, or in the synaptic cleft by inhibiting the transmitter reuptake or the main metabolic enzyme, MAO. The common final result, especially of chronic treatment, was the down-regulation of postsynaptic beta-receptors, modulated by interaction with the serotonergic system, neuropeptides, and hormones. The delay of clinical response corresponded better with such receptor alterations. However, the introduction of new, more selective antidepressants led to new reflections upon the mechanism of action. On the level of transmitters, alpha 1-upregulation, increased activity of the dopaminergic system, an alteration in the balance between the different transmitter systems, are reported and seem to be important. Most promising are recent investigations of the second messenger systems, the adenylate cyclase system and the phosphatidylinositol system. Both systems are modulated by antidepressant drugs including lithium and carbamazepine. These second messengers, in turn, modulate the phosphorylation status of neuronal proteins via protein kinase, which may lead to elevations of the above mentioned receptors and again their transduction systems.
Animals↗
Methodology of 3H-spiperone binding to lymphocytes.
Alterations in lymphocyte binding capacity for the dopamine antagonist 3H-spiperone may be of great interest in psychiatric and neurological disorders: an increase in capacity noted in lymphocytes of schizophrenic patients and their families may well turn out to be a phenotypic vulnerability marker. Since the 3H-spiperone binding assay with lymphocytes does not fulfill common receptor-binding assay criteria and depends more on crucial analytical conditions, shortcomings in binding assay might possibly lead to irreproducible results. A detailed methodological description of the binding assay and subsequent calculations has therefore been given in this paper.
Binding, Competitive↗
[Neurotransmitters in anxiety and panic disorders].
The currently available empirical findings lead us to assume that various forms of anxiety disorders--such as generalised anxiety syndrome or panic disorder--are based on different pathophysiological mechanisms with varying involvement of different neurotransmitter systems. We must bear in mind that whereas the disturbance of a transmitter may predominate--such as the disturbance of the noradrenalin system in panic disorder and that of the GABA-ergen system in generalised anxiety--on the other hand the transmitter systems are mutually interlinked, so that an isolated disturbance of a system is very unlikely. However, to the present date it has not been possible to give a definite biochemical characterisation of a certain disease pattern, such as that of panic disorder. Likewise, no unequivocal conclusions can be drawn in respect of cerebral localisation. Nevertheless, results obtained in animal experiments suggest that in panic disorder certain brain areas like e.g. the locus ceruleus may be affected. Future hopes rest in developing more specific drugs that selectively change a transmitter system and on new techniques such as positron emission tomography enabling a better insight into the mode of functioning of the brain. New possibilities seem to be offered also by defining a predisposition via molecular-genetic methods.
Anxiety Disorders↗
Clozapine--pharmacokinetic investigations and biochemical effects in man.
Clozapine with its unique pharmacological profile was investigated in different studies in order to elucidate its clinical-biochemical effects. Acute pharmacokinetic data showed a wide interindividual range with a mean halflife time of 6.0 h. The excretion pattern of catecholamines and their metabolites as well as hormone secretion were influenced in a different way. After 30 days of treatment, psychotic symptoms had markedly improved. However, only weak correlations were found to plasma levels. Side effects, such as sedation and orthostatic dysregulation, adapted and normalized during treatment. CSF-MHPG, CSF-5-HIAA decreased, CSF-HVA increased after 20 days of treatment indicating that the dopamine as well as the serotonin and noradrenaline systems are affected by Clozapine.
Biogenic Monoamines↗
Influence of CGP 361A, propranolol and diazepam on autonomous reactions to different stressors.
1. To evaluate the influence of beta-blockers and minor tranquilizers on autonomous stress response, 40 healthy subjects selected with regard to personality traits were randomly assigned to 5 groups. 2. Mental arithmetic induced the most pronounced increase in heart rate (HR), blood pressure and epinephrine secretion. 3. Beta-blockers reduced HR increases due to mental stress, whereas the minor tranquilizer reduced skin conductance level throughout the whole trial. 4. Our data provide evidence that different structured situations induce specific response patterns that are differentially modified by beta-blockers and minor tranquilizer.
Adrenergic beta-Antagonists↗
[Biological markers of endogenous psychoses].
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Genetic Markers↗
3H-spiperone binding sites in lymphocytes as possible vulnerability marker in schizophrenia.
The binding parameters for the dopamine antagonist 3H-spiperone to lymphocytes were investigated in nonmedicated schizophrenics (N = 43), in medicated schizophrenics (N = 25), as well as in 38 first- and second-degree relatives of schizophrenics, in a psychiatric control group (N = 27) and in normal, healthy controls (N = 40). The density of lymphocyte 3H-spiperone binding sites (Bmax) was significantly increased in all acute and chronic schizophrenic patients and in patients undergoing neuroleptic treatment for 2 weeks to several months and remained on a constant level during a drug-free remission period, suggesting that Bmax is a state independent variable. Elevated binding seems to be associated with schizophrenia; it could not be found in other psychiatric patients. In pedigree and family studies it became obvious that all relatives with one or more previous episodes of schizophrenia had similar increased binding capacity. But even in some well-state relatives elevated spiperone binding could be found, although they never had symptoms of the disease. Among these relatives of schizophrenics, there was an association between increased spiperone binding and the transmission of the disease. Although conclusive data about the precise genetic control obtainable in twin studies are still missing, we would suggest that elevated lymphocyte spiperone binding may be a marker of susceptibility to schizophrenia.
Adolescent↗
Zotepine, a neuroleptic drug with a bipolar therapeutic profile.
Zotepine, a new tricyclic compound, was investigated in 20 schizophrenic patients in two different dosage groups. Group I (n = 8) received Zotepine in a high dosage of 270 mg +/- 37 mg/die. The other group (group II; n = 12) received a low dosage of 168 mg +/- 15 mg/die. In both groups 2 patients dropped out before the end of the treatment period because of clinical deterioration. In both groups, Zotepine manifested a rapid antipsychotic effect, good tolerability, and sedative properties during the initial days. Additionally there was a stronger positive influence on negative symptoms in the group with low dosage treatment.
Adult↗
Reduced suppressor cell function in psychiatric patients.
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Acute Disease↗
Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788.
Noradrenaline (NA) plasma levels were examined in 18 healthy volunteers on 2 consecutive days after a single treatment with either lormetazepam (0.06 mg/kg) (LMZ group), flunitrazepam (0.03 mg/kg) (FNZ group) or placebo (PLA group) in combination with the benzodiazepine (BZ) antagonist Ro 15-1788 (0.1 mg/kg). Behavioural responses (mood changes, anxiety) were also investigated in parallel. Both BZ decreased NA plasma levels to 50% of the basal values 10 min after the injection; administration of Ro 15-1788 15 min later reinstated NA plasma levels to basal values. A second administration of Ro 15-1788 (0.1 mg/kg) 24 h after BZ or PLA treatment increased NA plasma levels, estimated 10 min after the injection in both the LMZ- and the FNZ groups, but not in the PLA group. Behavioural responses measured under the same treatment also indicated minor anxiety responses followed by mood impairment. These data suggest that a stressful situation may be precipitated by the antagonist Ro 15-1788 24 h after a single BZ treatment, which resembles a withdrawal response, and increases NA plasma levels.
Adult↗
Neuroendocrine effects of clonidine in chronic schizophrenic patients under long-term neuroleptic therapy and after drug withdrawal: relations to psychopathology.
The sensitivity of the alpha-adrenergic hypothalamic pituitary system, as indicated by growth hormone (GH) release after clonidine (0.15 mg i.v.), was studied in nine chronic schizophrenic in-patients (study 1) under long-term neuroleptic (NL) therapy and after 5 days' drug withdrawal and in 17 chronic schizophrenic in-patients (study 2) under long-term NL therapy and after 12 days' drug withdrawal. GH response after 5- and 12-day drug-free periods did not differ significantly from that under NL treatment; however, it was significantly lower after 12 days' drug withdrawal (AUC: 319.9 +/- 445.5 ng/ml X min) compared to age- and sex-matched normal controls (579 +/- 611 ng/ml X min). The basal norepinephrine (NE) plasma levels under long-term NL therapy were significantly elevated in both studies (study 1:894 +/- 553 pg/ml; study 2:432 +/- 268 pg/ml) compared to controls (study 1:253 +/- 55 pg/ml, study 2:234 +/- 126 pg/ml), and were decreased significantly after 5 days' drug withdrawal compared to NL treatment. There was no significant correlation between age, duration of NL therapy, last daily dosage, psychopathology, and NE plasma levels and GH response. The data presented suggest hyposensitivity of alpha-adrenergic receptor function in the hypothalamic-pituitary axis after 12 days' drug withdrawal in chronic schizophrenics. The significantly elevated NE plasma levels under NL therapy indicate that there is no adaption mechanism, even after long-term treatment.
Adult↗