Neuroleptic Side Effects: Acute Extrapyramidal Syndromes and Tardive Dyskinesia

Casey, Dympna; Keepers, George A.

doi:10.1007/978-3-642-73280-5_7

Cited by 58 publications

(37 citation statements)

References 52 publications

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“…The incidence of extrapyramidal symptoms in the present study was much lower than that associated with conventional neuroleptic therapy in the literature (Ortiz and Gershon, 1986;Keepers et al 1983;Casey and Keepers 1988). This observation is consistent with the findings of another short-term study where ziprasidone in doses up to 160 mg/day were shown to have lower potential to induce movement disorders than haloperidol 15 mg/day (Goff et al 1998).…”

Section: Discussionsupporting

confidence: 91%

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder A 6-Week Placebo-Controlled Trial

Daniel

1999

Neuropsychopharmacology

351

157

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is a novel antipsychotic with high affinity for dopamine D 2 and D 3 , serotonin 5HT 2A , 5HT 2C , and 5HT 1D receptors and high affinity for the 5HT 1A receptor, where it acts as a potent agonist (Seeger et al. 1995) (Table 1).Ziprasidone moderately inhibits 5HT and norepinephrine re-uptake into nerve terminals, has relatively modest affinity for histamine H 1 and adrenergic ␣ 1 receptors, low affinity for dopamine D 1 and ␣ 2 receptors, and negligible affinity for M 1 receptors.In vitro functional dopamine receptor antagonism by ziprasidone has been demonstrated by concentrationdependent blockade of effects induced by a D 2 agonist, quinpirole (inhibition of forskolin-stimulated adenylate cyclase) (Seeger et al. 1995). After systemic administration, ziprasidone produced relatively modest increases in dopamine metabolites as compared with haloperidol (Seeger et al. 1995).

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Section: Discussionsupporting

confidence: 91%

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder A 6-Week Placebo-Controlled Trial

Daniel

1999

Neuropsychopharmacology

351

157

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Section: The Aim Of the Present Study Was To Investigate The Relationmentioning

confidence: 99%

“…Clozapine is the prototypic atypical antipsychotic drug, and like chlorpromazine it interacts with a variety of dopamine and non-dopamine receptors (Meltzer et al 1989;Stockmeier et al 1993; Hacksell et al 1995). It is classified as an atypical antipsychotic because it is effective in the treatment of drug-resistant schizophrenia (Kane et al 1988) and not associated with the appearance of EPS (Casey 1989).The effects of the three drugs were investigated on EMG activity and related to their D 2 receptor occupancy in the striatum and substantia nigra, using the ex vivo method of Schotte et al (1993). Pilot experiments were conducted to establish the feasibility of the experimental approach and a preliminary report of some of these findings has been published Crocker 1996, 1997).…”

mentioning

confidence: 99%

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Hemsley

Crocker

1999

Neuropsychopharmacology

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The aim of the present study was to investigate the relationship between effects on muscle tone and D 2 receptor occupancy of two typical antipsychotic drugs, raclopride and chlorpromazine, and the atypical drug, clozapine. Increased muscle tone (i.e., muscle rigidity), was measured as increases in tonic electromyographic (EMG) The introduction of antipsychotic drugs has revolutionized the treatment of schizophrenia, but their use has been limited by the appearance of extrapyramidal side effects (EPS). These include acute dystonic reactions which appear early in treatment and are characterized by intense contractions of antagonistic muscles, and Parkinson-like side effects which include muscle rigidity and hypokinesia (Ayd 1961). It has been reported that 35% of drug noncompliance is due to the unacceptability of the side effects associated with antipsychotic drug treatment (Hoge et al. 1990) and this has stimulated a search for effective antipsychotic drugs which do not produce extrapyramidal side effects.The likelihood of extrapyramidal side effects developing appears to be dependent on the affinity of the antipsychotic drug for D 2 dopamine receptors (Creese et al. 1976;Seeman et al. 1976) so that there is a greater incidence associated with the high-potency drugs such as haloperidol and a lesser incidence with low-potency drugs such as chlorpromazine. Support for the view that there may be an association between the appearance of extrapyramidal side effects and D 2 receptor occupancy has come from positron emission tomography (PET) studies in humans (Farde and Nördström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995). These studies showed that EPS were associated with high D 2 receptor occupancy of 70%-89% in the striatum obtained with conventional doses of typical antipsychotics, but showed no association with D 1 occupancy. Importantly, clozapine whose (Farde and Nörd-ström 1992a;Farde et al. 1992b Farde et al. , 1992cNyberg et al. 1995).Despite being the subject of intense research interest, the mechanisms underlying drug-induced EPS remain unknown. One of the main factors contributing to this situation has been the lack of an objective, quantifiable experimental endpoint relevant to a cardinal feature of EPS, muscle rigidity, or increased muscle tone. We have developed an objective and quantifiable measure of muscle rigidity, assessed as changes in tonic electromyographic (EMG) activity in the anterior tibialis and gastrocnemius muscles of the hindlimb of conscious, unrestrained rats. We reported that tonic EMG activity is significantly increased in both muscles in an animal model of Parkinson's disease, namely following lesions of the ascending nigrostriatal dopaminergic neurons by bilateral 6-hydroxydopamine injections (Double and Crocker 1993). These EMG increases were significantly reduced by subcutaneous injection of the mixed D 1 /D 2 dopamine receptor agonist, apomorphine. Further work showed that both D 1 and D 2 dopamine receptors in the substantia nigra were involved in th...

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“…This raises the question as to whether these same benefits related to a lack of continuous D 2 occupancy might also carry over to long-term side effects which have been linked to prolonged D 2 blockade, specifically tardive dyskinesia (TD), a late-occurring motor side effect linked to acute EPS (Casey and Keepers, 1988). To this end, we recently found that only haloperidol administered through tri-weekly decanoate injections, but not daily intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Turrone

Remington

Kapur

et al. 2003

Neuropsychopharmacol

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Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D 2 receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D 2 receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D 2 receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n ¼ 36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D 2 occupancy levels were measured in vivo using [ 3 H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D 2 occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dosedependent D 2 occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D 2 occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.

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Neuroleptic Side Effects: Acute Extrapyramidal Syndromes and Tardive Dyskinesia

Cited by 58 publications

References 52 publications

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder A 6-Week Placebo-Controlled Trial

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder A 6-Week Placebo-Controlled Trial

Raclopride and Chlorpromazine, but not Clozapine, Increase Muscle Rigidity in the Rat Relationship with D2 Dopamine Receptor Occupancy

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

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