Remission of severe tardive dyskinesia in a schizophrenic patient treated with the atypical antipsychotic substance quetiapine

In a single inpatient case study, a schizophrenic patient with tardive dyskinesia after prolonged treatment with typical neuroleptics was treated with the new atypical neuroleptic quetiapine, a dibenzothiazepin-derivative. Within 2 weeks of treatment with quetiapine, symptoms of tardive dyskinesia improved; 10 weeks after starting treatment tardive dyskinesia stopped completely. Over the same period, dopamine D2 receptor occupancy decreased substantially, as measured by IBZM-SPECT after 14 and 77 days of treatment.     

Review article: metoclopramide and tardive dyskinesia

Background  Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long-term or high-dose use of this medication because of the risk of developing tardive dyskinesia.
Aims  To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide-induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug.
Methods  We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p-glycoprotein, risk factors, gastroparesis, outcome, natural history.
Results  Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 1–10% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications.
Conclusion  Community prevalence and pharmacogenetic mechanisms involved in metoclopramide-induced tardive dyskinesia require further study to define the benefit-risk ratio more clearly.     

Animal models of tardive dyskinesia--a review

Tardive dyskinesia is a serious motor side effect of long term neuroleptic therapy, with an unknown pathophysiological basis. The leading hypothesis of the pathophysiology of tardive dyskinesia includes dopamine receptor supersensitivity, GABAergic hypofunction, excitotoxicity and oxidative stress. Many preclinical models have been developed to identify the underlying pathological processes of tardive dyskinesia, but none has yet produced a parsimonious results. A wide range of animal models, viz. Homologous, analogous and correlational models have been developed to explore the pathophysiology of tardive dyskinesia. Vacuous chewing movements in rodents induced by chronic neuroleptic treatment is the most frequently employed model. As the existing models suffer from several phenomenological and methodological problems, development of new models, highly predictive of pathological basis of tardive dyskinesia can accelerate tardive dyskinesia research for the better understanding of the pathophysiological processes underlying the syndrome and for the discovery of new therapeutic targets for the treatment of tardive dyskinesia.     

Difference in catalepsy response in inbred rats during chronic haloperidol treatment is not predictive of the intensity of behavioral hypersensitivity which subsequently develops

An animal model was utilized to explore the observed clinical association between a history of significant neuroleptic-induced parkinsonism and an increased incidence for the subsequent development of tardive dyskinesia. Catalepsy-sensitive Fisher rats and catalepsy-resistant Brown Norway rats were treated for 14 days with haloperidol at a dose of either 1 mg/kg or 5 mg/kg daily. Following a 7-day drug withdrawal period, rats were tested for behavioral hypersensitivity to acute challenge with apomorphine and then striate were assayed for ³H-spiroperidol receptor binding. Despite significant interstrain difference in catalepsy response to either neuroleptic dose, Brown Norway rats treated with 5 mg/kg developed behavioral hypersensitivity and D-2 receptor supersensitivity equivalent to that of the similarly treated Fisher rats. Catalepsy, a possible rat analog for neuroleptic-induced parkinsonism, therefore did not predict the intensity of those subsequent behavioral and receptor changes considered to result from chronic antagonism of striatal dopamine receptors and to possibly underlie tardive dyskinesia. Further studies are required to elucidate the less than obvious relationship between extrapyramidal behavioral effects of chronic neuroleptic treatment.     

The effect of some new antidepressants on apomorphine-induced hypothermia in mice

Imipramine-like tricyclic antidepressants antagonize hypothermia induced by apomorphine in mice (Lapin & Samsonova 1968; Schelkunov 1968, 1977; Fuxe & Sjöqvist 1972; Maj et al 1974; Puech et al 1978); this phenomenon has been used by some authors as a test for the antidepressant activity. Therefore, we have examined the effect of some new antidepressants in this test, especially as some of them differ in their mechanism of action from imipramine-like drugs. The drugs used were: nomifensine, an inhibitor of the dopamine and noradrenaline (NA) uptake (Hunt et al 1974; Schacht & Heptner 1974), two specific inhibitors of 5-hydroxytryptamine (5-HT) uptake, femoxetine (FG 4963) (Buus Lassen et al 1975) and poroxetine (FG 7051) (Petersen et al 1977), two other antidepressants whose main characteristic was the blockade of central 5-HT receptors, i.e. mianserin (van Riezen 1972) and trazodone (Baran et al 1979). We also included pizotifen, a drug used in migraine prophylaxis (see Speight & Avery 1972) but exerting an antidepressant effect (Standal 1977; Banki 1978) and a potent central anti 5-HT activity (Dixon et al 1977; Przegalinski et al 1979). For comparison, the effect of four tricyclic antidepressants (imipramine, desipramine, amitriptyline and chlorimipramine) was also studied.     

Apomorphine-induced rotation in the unilateral 6-OHDA-lesioned rat: relationship to changes in striatal adenylate cyclase activity and 3H-spiperone binding

Rotational responses to apomorphine in rats with unilateral 6-hydroxydopamine lesions were significantly correlated with increases in ³H-spiperone binding but not with increases in DA-stimulated adenylate cyclase activity in lesioned striata. This behavioural index of DA receptor supersensitivity may be mediated by proliferation of those DA receptors that bind ³H-spiperone but are not linked to adenylate cyclase.Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway exhibit contralateral rotational behaviour when challenged with DA agonists Such as apomorphine. This behavioural supersensitivity has been shown to be accompanied by an increase in striatal ³H-haloperidol binding sites (Creese et al., 1977; Seeman et al., 1978). However, studies of the activity of striatal DA-sensitive adenylate cyclase (AC) after such lesions have produced conflicting results (Iversen, 1975; Krueger et al., 1976). While both of these biochemical measures have been proposed as in vitro indices of the DA receptor, recent data suggest they may reflect different types of receptor (Kebabian and Calne, 1979)- The behavioural significance of these two in vitro measures is at present unclear.In the present study we have used rotational response to apomorphine as a behavioural index of DA receptor supersensitivity after unilateral 6-OHDA lesion. In an attempt to determine the functional significance of the in vitro measures of DA receptor sites we have correlated changes in both DA-stimulated AC activity and ³H-spiperone binding in lesioned striata with their associated rotational responses to apomorphine.     

Naloxone prevents and blocks the emergence of neuroleptic-mediated oral stereotypic behaviors.

A commonly used animal model for tardive dyskinesia is the oral stereotypy that is expressed by a challenge dose of a dopamine agonist after daily administration of dopamine antagonists (neuroleptics). In the first of two experiments the expression of this dopamine agonist-induced oral stereotypy was prevented by the concomitant administration of the opiate antagonist naloxone. In a second experiment, if the stereotypy was allowed to be expressed, it could be blocked by the administration of naloxone. To the extent that the effects of chronic neuroleptic treatment in rats is a model for tardive dyskinesia, the results suggest that administration of naloxone can both prevent and block the dyskinetic syndrome associated with neuroleptic use.     

Effect of daily dose of chronic haloperidol and chronic apomorphine on behavioral hypersensitivity in the rat

Behavioral hypersensitivity in the rat consisting of increased dopamine-mediated stereotypic behaviors has been found to follow a 10-day course of treatment with the neuroleptic haloperidol as well as with the direct dopamine agonist apomorphine. The daily dose versus response relationship for chronic haloperidol indicates that a threshold daily dose exists and that behaviors increase with increasing daily dose. On the other hand, low rather than high daily doses of chronic apomorphine induce behavioral hypersensitivity and the response decreases with increasing daily dose. Prolonged functional denervation of striatal postsynaptic dopamine receptors by either neuroleptic blockade or autoreceptor stimulation may explain these findings. The results may help elucidate the relative risk of daily neuroleptic dose on tardive dyskinesia development and indicate a possible mechanism for chronic agonist-associated side effects likel-Dopa dyskinesias.     

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists.

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT₃ receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT₃ receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT₃ receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.     

Toxic rash associated with high dose methotrexate therapy.

Fifteen rashes were observed in thirteen patients in association with high dose methotrexate therapy. The lack of recurrence of the rash with further treatment courses and the association of the rash with other toxic manifestations and with larger doses of methotrexate suggests a toxic mechanism. Rashes have frequently been reported in association with dose methotrexate therapy (Van Scott, Auerbach & Weinstein, 1964; Leone, Albala & Rege, 1968; Mitchell et al., 1968; Capizzi et al., 1970; Jaffe et al., 1973; Rosen, Suwansirikul & Kwon, 1974; Pratt et al., 1975; Jaffe & Traggis, 1975; Ensminger & Frei, 1977; Stoller et al., 1977). They include perifolliculitis, transient erythema progressing to maculopapular eruptions, occasionally desquamating, sloughing over pressure areas, reactions confined to radiation portals, exacerbation of acne, photosensitivity and rarely urticaria. Relatively few reports sufficiently document the incidence or types of rash (Table 1). It has been suggested that the rash is allergic in nature (Mitchell et al., 1968) or a toxic phenomenon (Djerassi et al., 1972; Djerassi & Kim, 1976), possibly related to drug effects on small vessels (Van Scott, 1963).     

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.     

Possible involvement of prostaglandins in haloperidol-induced orofacial dyskinesia in rats

Dopaminergic abnormality is one of the pathological mechanisms involved in the pathophysiology of tardive dyskinesia, a late complication of neuroleptic treatment. Prostaglandins modulate the dopamine release in the striatum, the principle area involved in the pathophysiology of tardive dyskinesia. Rats were chronically treated with haloperidol (HPD) (1.5 mg/kg) for a period of 21 days, to induce orofacial dyskinesia. Behavioural assessment of orofacial dyskinesia was done 24 h after the last dose of haloperidol. Catalepsy was induced in rats by acute treatment with haloperidol (1 mg/kg), and catalepsy was scored for the next 4 h. Chronic haloperidol treatment induced profound vacuous chewing movements in rats. Indomethacin, a nonselective cyclooxygenase inhibitor dose-dependently (5–20 mg/kg) suppressed the vacuous chewing movements count in haloperidol-treated animals. In conclusion, the results of the present study infer that prostaglandins might play a significant role in the haloperidol-induced vacuous chewing movements, and prostaglandin synthesis inhibitors can serve as novel drug candidates for the treatment of tardive dyskinesia.     

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.     

Tardive dyskinesia and glucid metabolism

A role of insulin-dependent diabetes in the onset of tardive dyskinesia has been reported and relies on weak physiopathological evidence. OBJECTIVE: To study the relationship between the occurrence of tardive dyskinesia and variations in glucose levels in a population of patients under typical antipsychotic treatment. METHODS: Sixty-nine patients with a schizophrenic disorder and who had been receiving continuous neuroleptic treatment for at least 2 years were included. Tardive dyskinesias were assessed by the Abnormal Involuntary Movements Scale (AIMS) and glucose levels by glucose oxidase method. RESULTS: No significant differences in values of fasting glucose (FG) levels, post-prandial glucose (PPG) levels and glycosylated haemoglobin between the groups with and without tardive dyskinesia were found. In the sub-group with normal FG, comparison of post-prandial delta glucose levels (difference between PPG and FG) between the two group with and without tardive dyskinesia showed a significant difference (p < 0.05). This comparison also showed a correlation between post-prandial delta glucose levels and the AIMS score in the group with tardive dyskinesia (r = 0.482, p < 0.05). CONCLUSION: Glucose metabolism could be involved in patients with tardive dyskinesia. Various factors outside antipsychotic treatment can favour a disturbance of glucose metabolism, which may not be severe.     

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.     

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.     

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

Rationale Tardive dyskinesia is a syndrome of abnormal and involuntary movements which occurs as a complication of long-term neuroleptic therapy especially classical neuroleptics such as haloperidol and chlorpromazine. Dysfunction of GABA receptor mediated inhibition, and increased glutamatergic neurotransmission has been implicated in the development of orofacial dyskinesia in rats and tardive dyskinesia in humans. Neurosteroids modulate both GABAergic as well as glutamatergic neurotransmission in various brain areas. Objective The objective of the present study was to elucidate the role of various neurosteroids in neuroleptic-induced vacuous chewing movements and related behaviors in rats by using behavioral, biochemical, and neurochemical parameters. Materials and methods Animals chronically treated with haloperidol (1 mg/kg i.p.) for a period of 21 days exhibited marked increase in vacuous chewing movements, tongue protrusions, and facial jerkings as compared to vehicle-treated controls. It also resulted in increased superoxide anion levels and lipid peroxidation, whereas decreased levels of endogenous antioxidant enzymes (catalase and superoxide dismutase) in rat brain striatum homogenates. Neurochemical studies revealed that chronic administration of haloperidol resulted in significant decrease in the levels of dopamine, serotonin, and norepinephrine in rat brain striatum homogenates, whereas urine biogenic amines metabolite levels were increased. In a series of experiments, rats co-administered with allopregnanolone (0.5, 1, and 2 mg/kg i.p.) and progesterone (5, 10, and 20 mg/kg i.p.), both positive GABA-modulating [negative N-methyl-d-aspartate (NMDA)-modulating] neurosteroids prevented, whereas pregnenolone (0.5, 1, and 2 mg/kg i.p.) and dihydroxyepiandrosterone sulfate (0.5, 1, and 2 mg/kg i.p.) both negative GABA-modulating (positive NMDA-modulating) neurosteroids aggravated all the behavioral, biochemical, and neurochemical parameters. Conclusions These results suggest that neurosteroids may play a significant role in the pathophysiology of vacuous chewing movements and related behaviors by virtue of their action on either the GABA or NMDA modulation. Furthermore, neurosteroids showing selectivity for positive GABA modulation and/or negative NMDA modulation may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further evaluation.     

Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brain

Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.     

Prevention of neuroleptic-induced dopamine D2 receptor supersensitivity by chronic iron salt treatment.

The ability of neuroleptics to induce dopamine D2 receptor supersensitivity has been linked to the onset of tardive dyskinesia, the major side-effect of these drugs. Brain iron metabolism has been shown to be involved in the regulation of dopamine D2 receptors. We now examined the effect of chronic treatment with FeCl2 on chlorpromazine-induced D2 receptor supersensitivity. The results show that FeCl2 (5 mg/kg per day for 21 days) given to rats treated with chlorpromazine (10 mg/kg per day, for 21 days) prevented the onset of supersensitive biochemical and behavioral (apomorphine) expressions of DA D2 receptor. Inclusion of iron did not affect the chlorpromazine-induced sedation or hypothermia. Moreover, the combined chronic iron-chlorpromazine treatment produced the same net effects as chronic chlorpromazine on striatal amounts of dopamine, DOPAC (dihydroxyphenylacetic acid) and HVA (homovanillic acid). Chlorpromazine medication caused a decrease in liver non-haem iron levels (40%) but not in brain iron. The effect of the neuroleptic drug on iron stores and the involvement of iron in the neuroleptic-induced dopamine supersensitivity suggest that mobilization of iron from the periphery into the brain may play an important role in the mechanism of action of the neuroleptics.     

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.