Fluperlapine in tardive dyskinesia and parkinsonism

Fluperlapine, a new clozapine-like neuroleptic drug with weak affinity for dopamine receptors, was evaluated in a blind, placebo controlled trial in 11 patients with stable hyperkinesia (ten with tardive dyskinesia (TD) and one with spontaneous dyskinesia). Drug effects during active treatment (200–600 mg/day) and during pre- and post-treatment placebo periods were determined by scoring randomly sequenced videotapes of TD and parkinsonian symptoms recorded weekly during standardized examinations. TD score was unchanged, while parkinsonism slightly decreased (P<0.05) and eye-blinking rates increased (P<0.05). Psychiatric symptoms showed no significant changes, although positive psychotic symptoms diminished in four patients. Side effects included dizziness, sedation and constipation. The effects in movement disorders found in this study may imply that fluperlapine is less liable than traditional neuroleptics to induce acute extrapyramidal side effects and tardive dyskinesia and is particularly beneficial in the treatment of patients vulnerable to neurological side-effects.     

Effect of a cholinomimetric drug (RS 86) in tardive dyskinesia and drug-related parkinsonism

RS 86, a specific muscarinic agonist, was evaluated in a blind, placebo-controlled, single-dose trial in 10 psychiatric patients with stable tardive dyskinesia (TD). RS 86, 0.5–4 mg orally, produced no significant effects in TD, although 4 mg caused a minimal aggravation in parkinsonism. Side effects of the highest dose (4 mg) included hypersalivation (eight patients), nausea (6), sweating (3), and vomiting (3). It is concluded that treatmetn with RS 86 and probably other cholinomimetics has no or only limited beneficial effect in TD.     

Effect of baclofen on tardive dyskinesia

Eighteen chronic psychiatric patients with neuroleptic-induced tardive dyskinesia of 1/2–9 years duration participated in a double-blind crossover study on the effect and side effects of baclofen and placebo in the treatment of tardive dyskinesia. Each treatment phase lasted 3 weeks. Evaluation of the results included an assessment of video-tape recording. Baclofen (20–120 mg daily) reduced the hyperkinesias (median score from 5 to 3, P<0.05) and increased the parkinsonism (median score from 5 to 7, P<0.01). The effect on the oral movement pattern of tardive dyskinesia was characterized by a reduced frequency, an unchanged or slightly reduced amplitude, and an increased duration of each separate mouth opening and tongue protrusion, a response pattern very similar to the response pattern of -methyl-p-tyrosine, an inhibitor of the catecholamine synthesis. Sedation, muscular weakness, and confusion were observed in 50% of the patients. These side effects, appearing mainly in elderly patients, sometimes set in before the anti-hyperkinetic effect, thus limiting the practical usefulness of baclofen in the treatment of tardive dyskinesia.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Effects of tiapride in tardive dyskinesia

Tiapride, a selective D2 dopaminergic receptor blocking agent from the substituted benzamide class, was evaluated in a blind video-controlled trial in 10 psychiatric patients with tardive dyskinesia. There was a significant decrease in dyskinesia with a parallel increase in parkinsonism. This relationship between two opposite effects on movement suggests a common pathophysiological basis lying on a reciprocal hyper- and hypoactivity of the dopaminergic striatal system. Nevertheless, other mechanisms may be involved, for the evolution of individual parkinsonian and dyskinesia scores is not necessarily opposite: the tiapride-induced parkinsonism was generally acceptable and in two cases, the dyskinesia scores were reduced without an increase in parkinsonism. Therefore, more dyskinetic patients have to be evaluated in long-term studies with tiapride, before this drug could be recommended in tardive dyskinesia, when dyskinetic movements become intolerable.     

Haloperidol-induced tardive dyskinesia in monkeys

In three cebus monkeys the chronic daily administration of haloperidol (0.5 mg/kg/day orally) created sedation and parkinsonism during the first 5–7 weeks. Later the animals developed signs reminiscent of acute dystonia, as seen in the clinic during treatment with neuroleptics. These signs were dose-dependent and in extreme cases included widespread tonic and clonic seizures. After 3 and 12 months, respectively, two of the cebus monkeys developed buccolingual signs (grimacing and tongue protrusion), similar to tardive dyskinesia in the clinic.The tardive dyskinesia symptoms were reduced in a dose-dependent manner after each haloperidol administration, being most pronounced in the morning before haloperidol was given. Biperiden reduced acute dystonia but reinstated signs of tardive dyskinesia, which had been abolished by haloperidol. It is suggested that cebus monkeys may provide a useful animal model for the study of neurologic long-term complications from neuroleptic drugs.     

Clozapine in tardive dyskinesia

Clozapine, which has had limited clinical testing in the U.S.A., was evaluated in 12 chronic schizophrenic patients with tardive dyskinesia. Its antipsychotic activity was again demonstrated and it suppressed the symptoms of tardive dyskinesia with a marked rebound occurring in these symptoms when it was withdrawn; there was no rigidity or other Parkinsonian symptoms. However, out of a total of 12 patients, neutropenia (800 and 1120) occurred in two patients, convulsions in one patient, marked withdrawal effects in three patients, and a hypotensive collapse with atrial fibrillation in one patient. If these adverse effects are confirmed in a larger sample size, then despite the novel desirable effects of clozapine it would seem unlikely that it will gain widespread or routine use¹.     

Enkephalin,morphine, and naloxone in tardive dyskinesia

Eight psychiatric patients with tardive dyskinesia (TD) were treated with single doses of the synthetic met-enkephalin analogue FK 33-824 (1, 2, and 3 mg IM) morphine (10 mg SC) and naloxone, an opiate receptor antagonist (0.8 mg IM). The drug effects were assessed by blind evaluation of randomly sequenced videotapes made before and during treatment. FK 33-824 (1,2, and 3 mg IM) slightly reduced TD (P<0.05) and increased preexisting bradykinesia. The effect on TD, however, was pronounced only in patients concurrently treated with neuroleptics in relatively high doses. Morphine had a similar although weaker antihyperkinetic effect, whereas naloxone had no effect. Side effects of FK 33-824 included dizziness, heaviness in the extremities, slurred speech, and dryness of mouth. Morphine caused drowsiness, dizziness, ataxia, and nausea, and naloxone had no side effects. The results do not point to a primary role of enkephalin in the pathophysiology of TD, but enkephalin may interact with dopamine functions and potentiate some of the effects of neuroleptic drugs.     

The effect of drug holidays in an animal model of tardive dyskinesia

Intermittent haloperidol treatment in mice increased ³H-spiroperidol binding to the same degree as continual haloperidol feeding. The results do not support the concept that drug holidays can reduce the incidence of tardive dyskinesia.     

Pharmacokinetics and effects on prolactin of remoxipride in patients with tardive dyskinesia

The pharmacokinetics of remoxipride, a new selective dopamine-D₂ receptor antagonist with antipsychotic action, was evaluated in eight elderly psychiatric patients with tardive dyskinesia (TD). The daily oral doses of remoxipride were gradually increased from 50 mg per day to 200 mg t.i.d. over 2 weeks. The pharmacokinetics following the initial 50 mg dose (day 1) and the last 200 mg dose (day 15) of the drug were compared in serial samples. Plasma prolactin concentrations were assessed at the same time points. The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15. The mean dose corrected AUC values for the total concentrations were 96.8 at day 1 (4×24.2, 50 mg single oral dose) and 92.2 µmol·h/l at day 15 (200 mg). The unbound fraction of remoxipride calculated on AUC was slightly higher on day 15 (20%) than on day 1 (15%) (P<0.05), indicating slightly concentration-dependent protein binding of the drug. The mean elimination half-life of total remoxipride was slightly longer on day 15 than day 1 (7.5 versus 5.3 h,P<0.01) The corresponding half-lives for the unbound concentrations were 6.4 and 3.9 h, respectively (P<0.01). The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies. Following repeated administration of remoxipride, tolerance to the prolactin-releasing action of remoxipride is observed. In plots of the relationship between the concentration of remoxipride and the prolactin increase during a dosage interval, the curve on day 15 was positioned markedly to the right of that on day 1. This indicates a decreased sensitivity to the prolactin releasing action of remoxipride following continuous treatment.     

Chronic haloperidol produces a time- and dose-related slowing of lick rhythm in rats: implications for rodent models of tardive dyskinesia and neuroleptic-induced parkinsonism

 In order to characterize the development of orolingual motor effects of chronic haloperidol treatment in rats, this typical neuroleptic was administered for 102 days while daily measurements of tongue movement dynamics (peak force, lick rhythm, number of licks) during water licking were recorded. After chronic haloperidol dosing (vehicle, 0.06. 0.12, 0.24 mg/kg for four separate groups) for 32 days and continuing every second or third day of the chronic dosing period, the effects of cholinergic (scopolamine: 0.05–0.20 mg/kg; trihexyphenidyl: 0.15–1.0 mg/kg) or serotonergic (ritanserin: 0.5–4.0 mg/kg; quipazine: 0.5–4.0 mg/kg) probe drugs were examined for their capacity to antagonize the alterations in licking behavior induced by haloperidol. Haloperidol dose-dependently reduced peak force and number of licks, effects which were apparent within 2 or 3 days of the start of treatment. Significant effects of haloperidol on lick rhythm first emerged on day 13 and gradually increased in magnitude through the remaining treatment period. Scopolamine, trihexyphenidyl, and quipazine reduced haloperidol’s effects on at least one measure of licking behavior. During a 7-day haloperidol withdrawal period, the four dosage groups were similar on all measures of tongue dynamics. Overall, the results exhibited features suggesting the co-occurrence of Parkinson-like and tardive dyskinesia-like effects. Received: 3 July 1997 / Final version: 22 October 1997     

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. Offprint requests to: U. Andersson     

Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia

Oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. The resulting data was analyzed using fast-fourier analysis. Following an initial period of sedation (decreased energy at all frequencies), the drugged animals (and especially the FLU animals) began to show increased oral movements of 1–2 Hz, an effect which increased substantially upon drug withdrawal. This is precisely the altered energy spectrum observed in humans with tardive dyskinesia.     

Deanol in the treatment of tardive dyskinesia

Ten hospitalized chronic psychotic patients with symptoms of tardive dyskinesia were given deanol and placebo, each for 8 weeks following a double blind, crossover design. No psychotropic agents were administered during the trial. Improvement occurred in all patients during the first treatment phase regardless of which drug the patients received; seven patients were on deanol and three on placebo during this time. The possible reasons for this decrease were discussed. It was concluded that deanol may have contributed to the decline but that its effect on the disorder was not dramatic.     

Intra-patient variability in the measurement of tardive dyskinesia

Intra-patient variability in the movements of tardive dyskinesia was examined through the analyses of 8-min frequency counts collected over a period of 11 weeks for six chronic schizophrenic patients. Weekly observation segments of 8 min, 4 min, 2 min, 1 min and 30 s showed considerable variation both across weeks and within sessions. Variations were of sufficient magnitude to contribute to the possibility of false negative tardive dyskinesia assessments and false positive treatment outcome designations. Measurement procedures taking this variability into account are urged for the study of tardive dyskinesia. Additionally, independently obtained rating scale scores showed no association to the collected frequency count data, suggesting fundamental differences between these two assessment procedures.     

The treatment of tardive dyskinesia with baclofen

Thirty-one psychiatric outpatients with tardive dyskinesia (TD) on neuroleptic medication were followed in a double-blind, randomized trial comparing baclofen (30–90 mg per day) to placebo. A repeated measures analysis of variance revealed no statistical difference between the baclofen-treated group and the placebo group for the group and the placebo group for the total Abnormal Involuntary Movement Scale (AIMS) scores. There was a trend (P=0.09) for an initial improvement, then a worsening of frequency counts across four visits. The authors attempt to explain this finding on the basis of information obtained from animal research.UMDMJ-Rutgers Medical School and Department of Clinical Research, CIBA-GEIGY Corporation     

Extrapyramidal side effects of clozapine and haloperidol

Neuroleptic-induced extrapyramidal side effects (EPS) were evaluated in 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol followed in a drug monitoring program. Side effects were measured by the Columbia University Rating Scale, the Simpson Dyskinesia Scale and the Hillside Akathisia Scale. The cumulative incidence rate for tremor was found to be 24.4% in the clozapine group and 39.3% in the haloperidol group. This did not amount to a statistically significant group difference. Bradykinesia was observed in 21.8% of the patients treated with clozapine and in 47.7% of the patients of haloperidol (P=0.011). In the clozapine group the akathisia incidence rate was 5.6%, whereas haloperidol patients showed a higher rate of 31.7% (P=0.005). Our results show higher incidence rates of tremor and bradykinesia during clozapine treatment than previous studies. We conclude that clozapine is not entirely free of EPS, but they are usually less severe and of a different quality than side effects induced by typical antipsychotics.     

Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats

Rats were administered equivalent doses of haloperidol for either 28 days or 8 months using one of two different drug regimens: intermittent (i.e., weekly injections) or continuously (via drinking water and osmotic minipumps). Oral movements were determined by human observers and by a computerized video analysis system, which determined number and amplitude of jaw openings and closings (computer-scored movelets CSMs) as well as the slope (amplitude/duration) and frequency spectrum (fourier transform) of oral activity. The two drug groups developed distinctively different changes over time. Continuous administration resulted in late-onset oral activity changes at 1–3 Hz and withdrawal increases in CSMs, a pattern expected of tardive dyskinesia. Intermittent treatment produced a primed dystonia-like pattern: large amplitude CSMs which had steep onset slopes and a peak energy at 4–7 Hz. These results demonstrate the importance of drug regimen in determining the type of neuroleptic-induced dyskinesias which develop with prolonged neuroleptic treatment in rodents.     

Effect of scopolamine on visual attention in rats

Patients who develop persistent parkinsonism while on chronic neuroleptic therapy may be predisposed towards the development of tardive dyskinesia (TD). We investigated this issue in an animal model of TD by examining the association between catalepsy and the syndrome of neuroleptic-induced vacuous chewing movements (VCMs). VCMs were measured every 3 weeks for 33 weeks while rats received injections of haloperidol decanoate. Catalepsy was measured after the second through the seventh injections of the depot neuroleptic. There were no correlations between the severity of catalepsy scores after the second or third injections of haloperidol and the severity of the overall VCM syndrome. However, the severity of the catalepsy score following the third through seventh injections of haloperidol strongly correlated with the concurrent number of VCMs. Persistent high catalepsy scores across the six catalepsy rating sessions were strongly associated with the development of persistent severe VCMs. These findings suggest that, to the extent that persistent parkinsonian signs in humans are associated with a propensity towards the development of TD, the VCM syndrome in rats is at least a partially faithful animal model of this relationship.