Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol

 Late onset vacuous chewing movements (VCMs) from chronic neuroleptic treatment have been used as a rat model of tardive dyskinesia (TD). Early onset VCMs have also been observed, raising questions about the validity of this model. To assess the relationship between these two types of VCMs, pharmacological and neurochemical properties of early and late onset VCMs were compared. ”Acute” VCMs were induced by daily intraperitoneal injections for 1–21 days. ”Tardive” VCMs were induced by intramuscular injections of haloperidol decanoate every 3 weeks for 30 weeks followed by a 24-week withdrawal period. Suppression was attempted for both types of VCMs using several doses of intraperitoneal haloperidol. Striatonigral activation was assessed by measuring mRNA expression levels of the neuropeptides dynorphin and substance P using in situ hybridization histochemistry. Enkephalin mRNA was also measured as an index of striatopallidal activation. The results indicate that acute VCMs cannot be suppressed with increased doses of haloperidol and are associated with reduced dynorphin and substance P. This profile is similar to that seen with an animal model of parkinsonism. Tardive VCMs, in contrast, were markedly suppressed by haloperidol. They have previously been shown to be associated with increased striatonigral activation as indicated by increased dynorphin mRNA. Enkephalin mRNA was elevated following both short and long term treatment. Although superficially similar, acute and tardive VCMs appear to have different pharmacological and neurochemical profiles, suggesting they are related to acute extrapyramidal side effects and tardive dyskinesia, respectively. Received: 31 October 1995 / Final version: 23 May 1996     

Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia

Spontaneous adventitious oral movements which are produced in rats by very chronic (6- month) neuroleptic treatment have some phenomenologic and pharmacologic characteristics in common with tardive dyskinesia in humans. However, since not all of the features match, this putative model has been questioned and further support is warranted. Data from several laboratories support dichotomizing these neuroleptic-induced rat oral movements into “low”or “not TD-like” movements and “high”or “TD-like” movements, similar to the division of neuroleptic-induced involuntary movements in humans. Here, we have used mixture analysis to test this proposal statistically in 185 haloperidol-treated and 127 water-treated animals. Rats from several different studies were grouped together to form these two cohorts. The haloperidol dose, route of administration, rating technique, and balanced experimental groups were held constant across all experiments. Results show that two distinct groups of rat movements are induced by very chronic haloperidol treatment (1.5 mg/kg per day). The “low” vacuous chewing movement (VCM) group of rats had an average of 3.6 VCMs/5 min, and the “high” VCM group had an average of 16.1 VCMs/5 min; the conrol group, with a median VCM rate of 2.0 VCMs/5 min, demonstrated a single distribution. These data suggest that rats, like humans, dichotomize into two groups either expressing or not expressing “high” VCM dyskinesias with very chronic haloperidol treatment. Received: 5 November 1996 / Final version: 17 June 1997     

Ebselen attenuates haloperidol-induced orofacial dyskinesia and oxidative stress in rat brain

Haloperidol-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to basal ganglia oxidative stress. In this study the authors examined whether ebselen, an antioxidant organochalcogen with glutatione peroxidase-like activity, changes the behavioral and neurochemical effect of sub-chronic haloperidol administration. Haloperidol administered (12 mg/kg/week, sc) for 4 weeks caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the duration of facial twitching (FT) observed in 4 weekly evaluations (p<0.05). Ebselen (30 mg/kg, ip), administered every other day, along with haloperidol (12 mg/kg/week, sc) once weekly, reversed the increase of VCMs and FT in four weekly evaluations (p<0.05), while TP frequency was reverted in the 2nd, 3rd, and 4th week. After the treatments and behavioral observation, biochemical parameters in segments of the brain were analyzed. Haloperidol significantly increased the thiobarbituric acid-reactive species (TBARS) levels in the cortex, striatum and subcortical parts of the brain. The co-administration of ebselen reversed the effect of haloperidol on TBARS production in cortex and striatum. The results of the present study clearly indicate that ebselen has a protective role against haloperidol-induced orofacial dyskinesia and reverses the increase in TBARS production caused by haloperidol administration. Consequently, the use of ebselen as a therapeutic agent for the treatment of tardive dyskinesia should be considered.     

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.     

Neuroleptic-induced vacuous chewing movements as an animal model of tardive dyskinesia: a study in three rat strains

Vacuous chewing movements (VCMs) in three different rat strains developed at considerably different rates after 19 weeks of continual haloperidol treatment at an average daily dose of 1.5 mg/kg. Sprague Dawley (SD) rats displayed relatively high rates of VCMs with low variability, compared to Wistar (W) and Long Evan (LE) rats. Atropine decreased but did not abolish VCMs in two of the three strains (LE>SD). After haloperidol withdrawal, VCMs remitted gradually in all strains, but least rapidly in the SD rats. In a separate group of SD rats, VCMs were rated weekly from the start of haloperidol treatment and showed considerable interindividual variability. Even after 24 weeks of continuous haloperidol, 12 out of 32 treated rats showed no VCMs at all, while 13 out of 32 had intense movements, analogous to the clinical situation in which only some patients treated with neuroleptics develop tardive dyskinesia. These results indicate that there are individual and strain differences in the development of VCMs, and suggest that there may also be genetically determined differences in the development of tardive dyskinesia.     

The relationship between dopamine D2 receptor occupancy and the vacuous chewing movement syndrome in rats

Abstract Rationale. A dose–response relationship between dopamine D₂ occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear. Objectives. To ascertain the nature and extent of D₂ receptor occupancy effects on haloperidol-induced vacuous chewing movements (VCMs) in a rat model of TD. Methods. Groups of eight rats received haloperidol decanoate injections corresponding to daily doses of 0, 0.08, 0.17, 0.33, or 1 mg/kg for 10–12 weeks. VCMs were measured on a weekly basis and D₂ occupancy levels were measured in vivo using [³H]-raclopride at the end of the experiment. Results. Final VCM scores were significantly different between haloperidol doses (P=0.001). Moderate but significant correlations were found between dose and average VCM scores (r=0.69, P<0.001) and between D₂ occupancy and average VCM scores (r=0.65, P<0.001). The rats that developed the VCM syndrome (≥8 VCMs) had higher occupancies than rats that did not. Of the rats with an occupancy above 70%, 63% developed VCMs, compared with 37% of the rats with D₂ occupancy below that. Conclusions. These results indicate that chronic haloperidol induces VCMs in a dose-dependent manner, with doses leading to high D₂ occupancy increasing the likelihood of emergence of the VCM syndrome. While a certain level of D₂ occupancy may be necessary for inducing VCMs, it is not sufficient in and of itself to induce the VCM syndrome. Electronic Publication     

Involvement of adenosinergic receptor system in an animal model of tardive dyskinesia and associated behavioural, biochemical and neurochemical changes

Tardive dyskinesia is a syndrome characterized by repetitive involuntary movements usually involving the mouth, face and tongue. It is considered as the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Both, agonists of adenosine A(1) and A(2) receptors and the antagonists of A(2A) receptors are known to protect against neuronal damage caused by toxins as well as they can also protect against the cell damage inflicted by reactive oxygen species. The present study investigated the effect of adenosine and A(2A) receptor antagonist, caffeine in an animal model of tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypic rearing, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (superoxide dismutase and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose dependently inhibited by adenosine and caffeine. Chronic administration of haloperidol also resulted in an increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypic rearing after day 14. Chronic administration of haloperidol also decreased % retention time on elevated plus maze paradigm. Treatment with adenosine or caffeine reversed these behavioural changes. Besides, haloperidol also induced oxidative damage in all regions of brain which was prevented by caffeine and adenosine, especially in striatum. On chronic administration of haloperidol there was a decrease in dopamine and norepinephrine turnover which was dose-dependently reversed by treatment with adenosine or caffeine. When caffeine and adenosine were co-administered, there was no synergistic effect, possibly due to mutual antagonistic effects. The findings of the present study suggested the involvement of adenosinergic receptor system in the genesis of neuroleptic-induced tardive dyskinesia.     

Theophylline, adenosine receptor antagonist prevents behavioral, biochemical and neurochemical changes associated with an animal model of tardive dyskinesia

Tardive dyskinesia is considered to be the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Antagonists of A2A receptors are known to confer protection against neuronal damage caused by toxins and reactive oxygen species. The present study investigated the effect of adenosine receptor antagonist, theophylline (25 and 50 mg/kg, ip) in an animal model of tardive dyskinesia by using different behavioral (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 ip for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by theophylline. Chronic administration of haloperidol also resulted in the increased dopamine receptor sensitivity as evidenced by increased locomotor activity and stereotypic rearing. Further, it also decreased % retention time in elevated plus maze paradigm. Pretreatment with theophylline reversed these behavioral changes. Chronic administration of haloperidol also induced oxidative damage in all the brain regions which was prevented by theophylline, especially in the striatum. Chronic administration of haloperidol resulted in a decrease in dopamine levels which was reversed by treatment with theophylline (at higher doses). The findings of the present study suggested the involvement of adenosinergic receptor system in the development of tardive dyskinesia and possible therapeutic potential of theophylline in this disorder.     

Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia.

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.     

Effects of N-methyl-d-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias

Rationale Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma.Objective The objective of the present study was to elucidate the role of N-methyl-d-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats.Methods Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit.Results All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05).Conclusions These results suggest that NMDA receptors may play a significant role in the pathophysiology of tardive dyskinesia. Furthermore, antagonists showing selectivity for NMDA receptors containing the NR2B subunit may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further testing.     

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.     

Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: comparison with transient local inactivation

Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60 min of DBS (100 μA, 90 μs, 130 Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (-29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms.     

Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide

Tardive dyskinesia (TD) is a serious motor side-effect of chronic neuroleptic therapy. Chronic treatment with neuroleptics leads to the development of oral abnormal movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats have been widely accepted as an animal model of tardive dyskinesia. Chronic blockade of D2 inhibitory dopamine (DA) receptors localized on glutamatergic terminals in the striatum leads to the persistent enhanced release of glutamate that kills the striatal output neurons. The object of the present study was to explore the role of glutamatergic modulation on the neuroleptic-induced VCMs. Rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to produce VCMs. The neuroleptic-induced VCMs viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5 min observation period. Dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dose dependently (0.02 and 0.05 mg/kg) reduced haloperidol-induced VCMs. Felodipine (5 and 10 mg/kg), an L-type calcium-channel blocker, also significantly reduced the VCM count. N-omega-nitro-L-arginine methyl ester (L-NAME) (25 and 50 mg/kg), a nitric oxide synthase inhibitor, also reduced the VCM count in an L-arginine-sensitive manner. In conclusion, the findings of the present study indicated NMDA receptor involvement in haloperidol-induced VCMs, and also suggested the possible involvement of calcium and nitric oxide in haloperidol-induced VCMs.     

Quercetin,a bioflavonoid,attenuates haloperidol-induced orofacial dyskinesia

Chronic treatment with neuroleptics leads to the development of abnormal orofacial movements described as vacuous chewing movements (VCMs) in rats. Vacuous chewing movements in rodents are widely accepted as one of the animal models of tardive dyskinesia. Oxidative stress and the products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. In the present study chronic haloperidol (1.0 mg kg⁻¹ for 21 days) treatment induced vacuous chewing movements and tongue protrusions in rats. Co-administration of quercetin, a bioflavonoid, dose dependently (25–100 mg kg⁻¹) reduced haloperidol-induced vacuous chewing movements and tongue protrusions. Biochemical analysis revealed that chronic haloperidol treatment induces lipid peroxidation and decreases the glutathione (GSH) levels in the forebrains of rats. The antioxidant defense enzymes, superoxide dismutase (SOD) and catalase were also decreased due to chronic haloperidol treatment. Co-administration of quercetin (25–100 mg kg⁻¹) significantly reduced the lipid peroxidation and restored the decreased glutathione levels in these animals. Further quercetin (50–100 mg kg⁻¹) also reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. The major findings of the present study suggested that oxidative stress plays a significant role in neuroleptic-induced orofacial dyskinesia and quercetin co-administration reverses these behavioral and biochemical changes. Quercetin, a naturally occurring bioflavonoid could prove to be a useful agent in neuroleptic-induced orofacial dyskinesia.     

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.     

U-74500A (lazaroid), a 21-aminosteroid attenuates neuroleptic-induced orofacial dyskinesia

21-Aminosteroid, or lazaroid, is one of a novel class of antioxidant drugs designed to inhibit iron-dependent lipid peroxidation in biological lipid environments. They have shown promising results in several animal models of traumatic, ischemic and hemorrhagic injury of the central nervous system. Neuroleptic-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to oxidative stress in the basal ganglia. In this study, we have examined the protective role of U-74500A [pregna-1,4,9(11)-triene-3,20-dione, 21-(4-(5,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl)-16-ethyl-HCl (16-alpha)], a 21-aminosteroid having antioxidant property in attenuating the behavioral and biochemical effects of chronic haloperidol and chlorpromazine administration. Haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day i.p.) administered for 21 days caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the number of facial twitchings (FT) observed on day 22. U-74500A (1, 2 and 5 mg/kg i.p.), administered every day, along with haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day), attenuated the increase of VCMs and related behaviors on day 22. Haloperidol and chlorpromazine significantly increased lipid peroxidation in various brain areas such as the cortex, striatum and subcortical parts characterized by an increase in MDA levels. The coadministration of U-74500A limited the effect of haloperidol and chlorpromazine on MDA levels in the cortex and striatum but not in the subcortical parts. U-74500A, an aminosteroid, may have therapeutic use in typical neuroleptic-induced tardive dyskinesia-like 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.     

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.     

Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias.Part of this work was presented at the 9th C.I.N.P. Congress, Paris, July 7–12, 1974.     

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.