Striatal binding of 11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia: no evidence for altered dopamine D2 receptor binding.

Dopamine D2 receptor binding characteristics were studied by positron emission tomography (PET) using N-11C-methyl spiperone as receptor ligand in patients on longterm treatment with neuroleptic drugs and in control subjects. Eight of the patients had symptoms of tardive dyskinesia whereas three patients did not have any symptoms. Control subjects comprised 5 healthy volunteers and 7 patients with pituitary tumors. All patients had been free of neuroleptic drugs for at least 4 weeks. The time dependent regional radioactivity in the striatum was measured and the receptor binding rate, k3, proportional to receptor number, Bmax and association rate for the receptor was calculated in relation to the cerebellum. The lack in difference in k3 values between TD patients, neuroleptic treated patients without TD and control subjects throws doubt on the hypothesis that changes in striatal D2 dopamine receptor number or binding affinity is an etiological mechanism for persistent TD.

Neuropeptide changes in a primate model (Cebus apella) for tardive dyskinesia.

Tardive dyskinesia has been connected with regional reductions of GABA functions in the basal ganglia. In view of the possibility that peptides are involved in neuroleptic-induced dyskinesias substance P and dynorphin A levels were measured in the basal ganglia of the Cebus apella model for tardive dyskinesia. In addition, regional glutamate decarboxylase activities, dopamine, homovanillic acid and dihydroxyphenylacetic acid levels were monitored. A significant dyskinesia-related decrease in glutamate decarboxylase activity was found in the subthalamic nucleus, the medial segment of globus pallidus and the rostral part of substantia nigra in accordance with earlier findings. Cebus monkeys with an intact GABA system (neuroleptic-treated controls without dyskinesia) showed increased levels of substance P and homovanillic acid in the caudate nucleus. The changes were confined to the caudal part of the body of the caudate and the nucleus accumbens. On the other hand, the dyskinetic monkeys, with a defective GABA system, did not demonstrate a similar substance P rise in the caudate or nucleus accumbens, but showed a depression of homovanillic acid levels in the caudal part of the body of the caudate nucleus. Dynorphin A, dopamine and dihydroxyphenylacetic acid showed no dyskinesia-related changes. In conclusion, the difference in glutamate decarboxylase activity between animals developing dyskinetic symptoms vs those who did not, was reflected by regional changes in substance P and homovanillic acid levels.

Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia.

Glutamate decarboxylase (GAD) activity was measured in the nuclei of the basal ganglia in patients with neuroleptic-induced tardive dyskinesia (TD) and controls matched for age and premortem state. In five TD patients, who all had a sudden death, a significant decrease in GAD activity was found in the subthalamic nucleus (STN). The lowered GAD activity in the STN may represent a biochemical substrate for neuroleptic-induced TD.

Neurobiochemical changes in tardive dyskinesia.

There is evidence for the view that both up- and downregulation of nigral GABA may give rise to dyskinetic movements. Intranigral infusion of GABA agonists causes stereotyped licking and gnawing in rats, while intranigral GABA antagonists produce vacuous chewing movements. It is hypothesized that during long-term neuroleptic treatment there may be a succession of changes within striatonigral GABA neurons: down-regulation caused by neuroleptic drugs may increase receptor sensitivity, and this may lead to overcompensation and withdrawal dyskinesia during periods of cessation of drug treatment. Reduced nigral GAD activity may be a marker of irreversible brain damage and has not been observed in all chronic experiments, but only in individuals with long-standing or irreversible dyskinesia. Changes within the GABA system seem to be accompanied by changes in the striatal and nigral levels of substance P.

Remoxipride, a selective dopamine D2 receptor antagonist, in tardive dyskinesia.

Remoxipride in a dose range of 150-600 mg/day was evaluated in a single-blind placebo controlled study in eight patients with persistent tardive dyskinesia (TD). Dyskinesia score was significantly reduced without an increase in parkinsonism. The maximum mean reduction in dyskinesia rating score was 44%. After withdrawal of remoxipride TD scores returned to baseline levels without rebound deterioration. A negative correlation between remoxipride concentrations and the dyskinesia scores were found. Adverse effects were few and mild and no clinically relevant changes were seen in clinical chemistry, haematology or cardiovascular assessments. It is concluded that remoxipride in the dose range used has anti-dyskinetic effects but does not induce parkinsonism.

GABA agonists in cebus monkeys with neuroleptic-induced persistent dyskinesias.

Tetrahydroisoxazolopyridinol (THIP), a GABA receptor agonist, gamma-acetylenic-GABA(GAG) and gamma-vinyl-GABA(GVG), two GABA transaminase inhibitors were given in single parenteral doses to three Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol. High doses of THIP temporarily abolished dyskinesias but also caused bradykinesia, ataxia, dystonia and myoclonic jerks. GAG and GVG reduced dyskinesias to a lesser extent and with fewer side effects. Whether the observed antidyskinetic effect is secondary to the concomitant general toxic effects or if these drugs have a specific antidyskinetic action remains an open question.

Experimental tardive dyskinesia.

In ongoing studies of chronic administration of neuroleptics to monkeys (Cebus apella) and rats, the regional distribution of glutamic acid decarboxylase (GAD) and brain levels of homovanillic acid were examined. Reduction of GAD activity, a GABA-synthesizing enzyme, in three specific brain areas (substantia nigra, medial globus pallidus, and nucleus subthalamicus) was related to the development of neuroleptic induced dyskinesias; these reductions were not seen in treated animals who did not develop movement disorders. The neostriatal level of HVA was reduced in dyskinetic monkeys. Such animal models can be useful in the screening process for new antipsychotics and thus potentially aid in the prevention of drug-induced tardive dyskinesia.

Pathophysiology of tardive dyskinesia.

Animal models of persisting tardive dyskinesia have been developed in two species (rats and monkeys). Dyskinetic animals chronically treated with neuroleptics had significant decreases in glutamic acid decarboxylase and GABA in the substantia nigra, the medial globus pallidus, and the subthalamic nucleus, whereas animals without dyskinesias which had been treated similarly had a normal distribution of these biochemical parameters. These changes remained 2 months after neuroleptics were discontinued, and at that point there was a reduced turnover of striatal dopamine in the dyskinetic monkeys. These findings suggest that reduced GABA function in the substantia nigra may play a role in tardive dyskinesia.

Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis.

The movement disorder tardive dyskinesia is a serious side effect of the long-term treatment of schizophrenia with neuroleptic drugs. Similar symptoms to those of tardive dyskinesia have been observed in Cebus apella monkeys following long-term treatment with neuroleptic drugs, and these monkeys may therefore be a useful animal model of tardive dyskinesia. Motor defects have persisted in these dyskinetic monkeys for periods of 1-6 yr after the cessation of neuroleptic treatment. We report here that in three regions of the brains of dyskinetic monkeys (substantia nigra, medial globus pallidus and subthalamic nucleus) glutamate decarboxylase activities and gamma-aminobutyric acid (GABA) levels are reduced relative to control monkeys that had been treated with neuroleptics but which showed none of the symptoms of tardive dyskinesia. These results suggest that alterations in the GABA neurone system are involved in neuroleptic drug-induced tardive dyskinesia.

Tardive dyskinesia associated with metoclopramide.

Eleven cases of tardive dyskinesia associated with metoclopramide have been reported to the Swedish Adverse Drug Reactions Advisory Committee from 1977 to 1981, 10 of which developed during the past three years. All patients were women, with a mean age of 76 years. Median duration of treatment before the onset of symptoms was 14 months. Calculated from total drug sales and prescription statistics the incidence of tardive dyskinesia during treatment with metoclopramide was estimated to be one in 2000-2800 treatment years. Extrapolation of data on long term treatment (more than six months) of patients aged 70 years or more, from a survey based on individual prescriptions yielded an incidence of more than one in a 1000 patients. Long term treatment with metoclopramide is accompanied by a substantial risk of developing tardive dyskinesia especially among elderly people.

Effects of sulpiride on persistent neuroleptic-induced dyskinesia in monkeys.

Five Cebus apella monkeys with persistent neuroleptic-induced dyskinesia were given a single dose of sulpiride (20 mg/kg i.m.). The dyskinesia was reduced in all five although four developed attacks of acute dystonia which had to be reversed by anticholinergic medication in three animals. In one monkey the administration of classic neuroleptics had earlier been shown to induce a typical sequence of events. First there was a similar reduction of dyskinesia as seen in the other monkeys, 1-2 days later there was noticed a rebound deterioration lasting for several days. Metoclopramide 0.5 mg/kg, caused such a rebound effect (for 2 days), whereas sulpiride did not.

Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress.

Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and gamma-amino-butyric acid (GABA) in discrete regions from 7 drug-naive control monkeys. Also data from the stressed animal are presented.

Application of a primate model for tardive dyskinesia.

Persistent signs of oral dyskinesia (tongue protrusion and facial grimacing) had developed as a result of earlier chronic treatment with neuroleptics in a Cebus apella monkey. When this animal was given single doses of any classical neuroleptic, a transient deterioration of dyskinesia occurred, preceded by a temporary abolishment of dyskinesia sometimes with an attack of acute dystonia. Fluphenazine (5-25 micrograms/kg) causes dose-related deteriorations of dyskinesia. Six different drugs were tested on this monkey for their capacity to elicit aggravation of dyskinetic signs: three antihistamines (brompheniramine, promethazine, diphenhydramine) and three dopamine D2 receptor antagonists (sulpiride, tiapride, metoclopramide). High doses of promethazine and diphenhydramine (5 mg/kg) induced a temporary alleviation of dyskinesia, possibly through sedation. All three D2 receptor antagonists precipitated signs of acute dystonia at some dose levels, but out of the test drugs only metoclopramide caused deterioration of dyskinetic symptoms. According to the present results only metoclopramide stands out as a drug with an inherent propensity to cause tardive dyskinesia.

Antidyskinetic action of 3-PPP, a selective dopaminergic autoreceptor agonist, in Cebus monkeys with persistent neuroleptic-induced dyskinesias.

Four Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol were subjected to a trial of the dyskinesia-modifying effects of a novel dopamine autoreceptor agonist 3-PPP (3[3-hydroxyphenyl]-N-n-propyl-piperidine). Three monkeys had choreic dyskinesia involving trunk and extremities whereas one had a buccolingual form including tongue protrusion with choreoathetotic twitching and twisting movements of the tongue. Two monkeys (1 choreic, 1 buccolingual) responded with dose-dependent symptom alleviation to 3-PPP, 1-4 mg/kg, with no signs of concomitant sedation or catalepsy. In the monkey with buccolingual dyskinesia all dyskinetic signs disappeared completely 2 hours after 2 mg/kg of 3-PPP. This animal participated in a separate study where the same doses of 3-PPP but also its enantiomers were given. The (-) enantiomer was a more potent antidyskinetic agent than the (+) enantiomer, the racemate falling between these two. Four mg/kg of the (+) enantiomer precipitated an amphetamine-like excitation and after 4 hours aggravation of dyskinesia was noted. These observations support the notion that the (+) enantiomer has both postsynaptic and presynaptic stimulatory effects, whereas the (-) enantiomer acts as a presynaptic dopamine receptor agonist.

Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced oral dyskinesia.

Following eight monthly haloperidol decanoate injections rats showed an increased rate of vacuous chewing movements (VCM's), which gradually disappeared within 4 drug-free months. Another single dose of non-decanoate haloperidol reinstated a second increase in VCM rate which was still significant after 2 months. The glutamic acid decarboxylase (GAD) activity in the substantia nigra of these chronically haloperidol-treated rats was lower than untreated controls. Furthermore, there was a significant negative correlation between individual VCM rates and nigral GAD activity. No corresponding changes occurred in other brain regions. The depression of nigral GAD may reflect a reduced tissue density of GABA-ergic axon terminals within the descending striato-nigral pathway.

Serum concentrations of thioridazine, its major metabolites and serum neuroleptic-like activities in schizophrenics with and without tardive dyskinesia.

Two groups of elderly chronic schizophrenic patients, one with and one without tardive dyskinesia (TD), were studied. In addition to estimation of the neuroleptic-like radioreceptor activity (RRA) of the serum, serum concentrations of thioridazine (THD) and its major metabolites, THD-2-sulfoxide, THD-2-sulfone and THD-5-oxide, were measured with high performance liquid chromatography. Blood samples were collected at two different occasions when the patients were considered to be in a pharmacological "steady state". The concentrations of THD and its metabolites, as well as RRA values, were similar at both occasions. In general, THD-2-sulfoxide and THD-5-oxide were present in higher concentrations than the parent compounds, and the serum concentrations of THD, its metabolites and the RRA values were positively correlated with the administered daily dose of THD. However, no significant difference in serum levels of THD, its metabolites, or significant difference in serum levels of THD, its metabolites, or RRA values existed between the patients with and without TD. These data suggest that pharmacodynamic rather than pharmacokinetic differences may be more important in producing high risk for TD in patients on long-term neuroleptic treatment.

Bromocriptine in tardive dyskinesia.

Five schizophrenics and one alcoholic with tardive dyskinesia were given bromocriptine for two 8-week periods. The first trial was made during neuroleptic treatment and the second following a 3 weeks' wash-out of neuroleptics. When neuroleptics were given bromocriptine was essentially without effects, but after the neuroleptics had been discontinued the same bromocriptine treatment caused amelioration of dyskinesia in three and aggravation in two subjects. During the second bromocriptine trial all schizophrenic patients showed deterioration of psychotic symptoms followed by a reduction of symptoms when bromocriptine was discontinued.