Psychopharmacology. Supplementum最新文献

The reported prevalence of tardive dyskinesia (TD) widely ranges from 0.5% to 70%. This variability is probably due to many factors, including different patient characteristics, drug treatment exposures, and investigator biases. The aim of this study was to evaluate the prevalence, severity, and symptom type of TD in all 646 patients residing in a psychiatric hospital. Each patient was assessed by a psychiatrist and a neurologist with a special rating scale after drug dose had been stabilized for a minimum of 1 week. The overall prevalence was 32%, with a slightly higher rate and more severe symptoms in women. Age positively correlated with increasing prevalence and severity of TD. Psychiatric diagnosis and duration of neuroleptic therapy were not significantly correlated with TD prevalence. The results are generally consistent with the majority of findings in other studies of the epidemiology of TD.

Two different studies were performed in subhuman primates in an attempt to induce symptoms of tardive dyskinesia. The first study lasted for over 5 years. This involved elderly Macaca speciosa. The animals were given first 25 mg of fluphenazine decanoate and later the enanthate IM (3.2 mg/kg) every 2 weeks and on 5 days a week, haloperidol, first IM and later PO. Haloperidol was given first in doses of 1.0 mg/kg and ultimately after years of therapy, in doses of 6.4 mg/kg per day. Those animals who survived gained weight to over 10 kg. After neuroleptic withdrawal, tardive dyskinesia became evident in 1 month. The symptoms of tardive dyskinesia following cessation of medication lasted a maximum of 1 year. This animal model produced very impressive symptoms in one of the three animals treated who survived. This is not a very practical animal model from the aspects of economics (costly), time (5 years), and animal availability (rare and endangered species). However, the symptoms of tardive dyskinesia are very striking and identical with human tardive dyskinesia in a susceptible animal. A more practical experimental animal model involved Cebus apella. Depot fluphenazine (0.1 to 3.2 mg/kg) was given continuously every 2 weeks for 1 year. In this species the symptoms of tardive dyskinesia became progressively prolonged and intense with each course of fluphenazine therapy and withdrawal, suggesting that reversible tardive dyskinesia may turn into irreversible tardive dyskinesia. With each succeeding course of fluphenazine therapy (1 month) and withdrawal (1-3 months), the animals appeared to be sensitized to both the acute extrapyramidal and the tardive dyskinesia symptoms. These animals were also given various experimental drug treatments including biperiden lactate, benztropine mesylate, and d-amphetamine after they developed signs of tardive dyskinesia.

Tardive dyskinesia remains a major concern in psychiatry. Epidemiologic data suggest that the prevalence of the disorder has increased over the past two decades. The average prevalence of TD across various populations is 15%-20%. Abnormal involuntary movements appear to be at least three times more prevalent in neuroleptic-treated patients than in patients not exposed to such drugs. The incidence of TD in a young adult (mean age 27) population is 14% after 4 years of cumulative neuroleptic exposure. The majority of these cases are mild and the condition does not appear to progress in most individuals despite continued neuroleptic exposure. Age remains the single most important risk factor for the development of TD. Recent investigations suggest that patients with affective illness may also be more vulnerable.

Abnormal involuntary movements (AIMs, stereotyped or dyskinetic movements) were induced with different dopamine mimetics in rat, cat, and monkey. In the rat only stereotyped movements were observed, whereas in the cat dopamine agonists (apomorphine) preferentially induced dyskinesia but dopamine/noradrenaline uptake inhibitors (d-amphetamine, nomifensine) induced predominantly stereotypes; L-dopa induced an equal, low, number of both kinds of movements in the cat. In the monkey with bilateral lesions of the nigrostriatal dopamine pathways the AIMs could be divided into type 1 dyskinesia (behavioral), type 2 dyskinesia (oral and psychomotor), and chorea. GABA agonists (progabide, muscimol) had a biphasic action on apomorphine stereotypes in the rat, slightly (10%-20%) augmenting these movements at low doses and antagonizing (greater than 50%) them at higher doses. As these latter doses of progabide also antagonize apomorphine-induced circling in rats with a unilateral lesion of the substantia nigra, it is likely that this action is exerted at or beyond the dopamine target cell. In cats the dyskinetic movements induced by apomorphine were abolished by progabide. In contrast, L-dopa-induced stereotypies were resistant to the antidyskinetic action of progabide, and at low doses of L-dopa an increased incidence of stereotypies was noted. In the monkey, the type 1 dyskinesia following L-dopa and piribedil were also relatively resistant to progabide administration, whereas the type 2 dyskinesia and chorea were abolished by progabide. These studies are parallel to and support the clinical observations that dyskinetic movements following a direct action at the dopamine receptor (tardive dyskinesia) may be reversed by progabide whereas those associated with dopamine neuron activity, perhaps together with noradrenergic activation (L-dopa dyskinesia), are resistant to the antidyskinetic action of progabide.

Among the various deficiencies in neurotransmitters and neuropeptides in the brains of patients with Parkinson's disease, the loss of dopamine (DA) is implicated in a major way in the occurrence of L-dopa-induced abnormal involuntary movements (AIMs). Whatever the clinical pattern, they are triggered by drugs which stimulate DA transmission and can be modified by DA agonists and antagonists. They occur when DOPA plasma concentrations, and thus central DA receptor stimulation, reach a critical level. They are observed in patients with severely damaged central DA neurons, but involvement of other neurotransmitter-containing cells cannot be excluded. L-Dopa-induced AIMs have clinical and somatotopic characteristics, which vary from patient to patient. One might speculate that variable damage to DA neurons, associated or not with other neurotransmitter-containing cells in the affected brain structures, causes these differences in AIM patterns. By analogy with behavioral experiments in animals, the hypersensitivity of DA receptors observed in the basal ganglia of parkinsonian patients post mortem might reasonably be considered to mediate L-dopa-induced AIMs. However, the role of various subtypes of DA receptors or of changes in DA metabolism in the cell bodies and dendrites (substantia nigra) or nerve terminals (striatolimbic areas) must also be considered. In brief, the features, topography, and timing of L-dopa-induced AIMs are dependent upon alterations of the functional expression of striatal DA output, which is not yet well understood.

Movement abnormalities in neuroleptic-treated, psychiatric patients are classified as (a) initial syndromes, including dystonia, parkinsonism, and hyperkinetic abnormalities such as initial dyskinesia (ID) and akathisia, all of which are related to the neuroleptic dose and can be considered as overdose phenomena; (b) tardive syndromes, mainly the classic tardive dyskinesia (TD) syndrome, more seldom tardive akathisia and tardive dystonia, which may all develop or aggravate after withdrawal of neuroleptic treatment; and (c) age-related, spontaneous dyskinesia, akathisia, and dystonia, and schizophrenia-related, hyperkinetic, often stereotyped, movements and restlessness. ID and TD can occur simultaneously, and may depend, at least partially, on identical mechanisms. The pathophysiology of TD is still not clear, and the traditional dopamine (DA) hypersensitivity model seems inadequate. Animal experiments suggest that blockade of some DA receptors in the brain (e.g., in ventromedian striatum) may counteract hyperkinesia and produce parkinsonism, while a concomitant blockade of other similar receptors in other brain regions (e.g., in anterodorsal striatum) may aggravate movements. This offers an explanation for the concomitant occurrence of parkinsonism and hyperkinetic movement abnormalities (ID and akathisia) relatively early in a neuroleptic treatment, and may also contribute to the understanding of the pathophysiology of TD. It is concluded that pathophysiologically TD is a heterogeneous syndrome depending on a subtle balance between several neurotransmitters in the brain, including DA receptor blockade and hypersensitivity of DA and GABA receptors.

Rats received haloperidol, sulpiride, or clozapine in their daily drinking water for up to 1 year in clinically equivalent doses. After 12 months' drug intake, and while drug administration continued, striatal dopamine function was assessed. Haloperidol induced D-2 receptor hypersensitivity as shown by enhanced apomorphine-induced stereotypy, elevated Bmax for specific 3H-spiperone and 3H-NPA binding, and an increase in striatal acetylcholine content. D-1 receptor sites appeared unaffected, since dopamine-stimulated adenylate cyclase and specific 3H-piflutixol binding were not altered. In contrast, neither sulpiride nor clozapine enhanced apomorphine-induced stereotypy or increased Bmax for 3H-spiperone binding. Sulpiride, but not clozapine, increased Bmax for 3H-NPA binding; clozapine, but not sulpiride, elevated striatal acetyl choline concentrations. In general, both sulpiride and clozapine enhanced D-1 function as assessed by dopamine-stimulated adenylate cyclase or 3H-piflutixol binding. On acute administration sulpiride and clozapine appear to act at D-2 sites, but continuous chronic administration of these compounds does not result in the development of striatal D-2 receptor hypersensitivity. The absence of change in D-2 function during chronic treatment, coupled with an ability to enhance D-1 function, may contribute to the low incidence of tardive dyskinesia produced by these drugs in man.

Subjects and methods: 54 healthy volunteers took part in 3 placebo controlled double-blind trials designed partly as crossover, partly as parallel group studies. The long-acting (elimination half-life greater than 24 h) test drugs diazepam (DIA 5; 10 mg) and flurazepam (FLU 30 mg) were compared to the short-acting drugs (elimination half-life less than 12 h) lormetazepam (LOR 1.5; 2 mg) and mepindolol sulfate (MEP 10 mg; betablocker) following acute or subchronic application. Alcohol (ALC; 0.4-0.8 per mill blood ALC concentration) was used as a compound interfering with the test drugs. Measurements with the driving simulator TS2 were taken at different times between 1 h and 15 h p.a.

Results: Subchronic use of FLU causes significant impairment of driving performance the next morning in contrast to LOR which even increases the driving ability. The ALC potentiating effect of LOR is larger than that of DIA after acute intake. MEP acts like placebo but reduces blood pressure and heart rate. Interaction of LOR and ALC in the evening does not result in a prolonged hangover effect which could disturb driving performance the next morning.

Discussion: Short-acting benzodiazepines without active metabolites have a profound advantage over those with long-acting accumulating characteristics in respect to matutinal car driving ability, if those drugs are used as nighttime hypnotics. These results highlight the necessity of screening hypnotic and tranquilizing drugs concerning their influence on car driving performance at different times after intake and under conditions of interactions with psychotropic drugs, especially alcohol. In view of future methodological requirements a revised model of driving simulation is presented. It is based on a coherent description of the system "driver-vehicle environment" at the level of visual conditions, vehicle behaviour and driver performance. Preliminary data are shown.