Extrapyramidal Disorders After Prolonged Phenothiazine Therapy

Kennedy, Peter; Hershon, H. I.; McGuire, Ross

doi:10.1192/bjp.118.546.509

Cited by 95 publications

(24 citation statements)

References 6 publications

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“…Neuroleptic drug treatment in humans can cause several motor dysfunctions, some of which are persistent or irreversible (Ayd, 196 1;Druckman et al, 1962;Crane et al, 1971;Kennedy et al, 1971;Burke et al, 1982). These include tardive dyskinesia and acute and late-onset dystonias.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

1995

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The morphological effects of several neuroleptics as well as other novel and prototypic sigma ligands were examined by addition to cultures of C6 glioma cells. Sigma ligands caused loss of processes, assumption of spherical shape, and cessation of cell division. The time course and magnitude of this effect were dependent on the concentration of sigma ligand. Continued exposure to sigma compounds ultimately resulted in cell death. However, the morphological effect was reversible when sigma ligand was removed shortly after rounding. The potency of compounds to produce these effects generally correlated with binding affinity at sigma receptors of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a concentration of 100 microM, haloperidol, reduced haloperidol, fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and SH344 produced significant effects in 3–6 hr of exposure. Other compounds, such as trifluperidol, thioridazine, and (-)-butaclamol, produced significant effects by 24 hr of exposure. Despite the requirement of micromolar concentrations of ligand (some compounds were effective at 30 microM), the effect showed a remarkable specificity for compounds exhibiting sigma receptor binding affinity. Neuroleptics lacking potent sigma affinity [e.g., (-)- sulpiride, (+)-butaclamol, and clozapine] and other compounds that lack significant sigma affinity but that are agonists or antagonists at dopamine, serotonin, adrenergic, glutamate, phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were without effect on cellular morphology at concentrations up to 300 microM over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG), (+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP], (+)-pentazocine, (+)- cyclazocine, and other sigma-active benzomorphans and morphinans appeared inactive in up to 72 hr of culture. However, these compounds interacted synergistically with a subeffective dose of BD737 (30 microM) to produce effects usually in 6 hr or less. Also, the pH of the culture medium had a profound effect on the activity of sigma compounds. Increasing the pH from the normal range of 7.2–7.4 to pH 8.3– 8.5 shifted the dose curves (30, 100, 300 microM) for all sigma compounds to the left. Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionmentioning

confidence: 99%

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

1995

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“…Neuroleptic-induced Parkinsonism is common; the lowest estimate is 23% (Ayd, 1961), but Kennedy et al (1971) found that 88% of chronic schizophrenics after at least three months of treatment with a phenothiazine had tremor, and 68% had rigidity. Many studies of drug-induced Parkinsonism have employed techniques somewhat different from those in idiopathic Parkinson's disease.…”

Section: Ticsmentioning

confidence: 99%

“…It is fairly simple to apply, the terms used are clearly defined, and there is a standardised examination procedure. The scale includes global assessments of severity (both by the patient and the observer) and dyskinesia scores for the face, lips, jaw, tongue and limbs, as well as a functional disability score (see also Kennedy, Hershon & McGuire, 1971).…”

Section: Ticsmentioning

confidence: 99%

Assessment of extrapyramidal disorders.

Marsden¹,

Schächter²

1981

Brit J Clinical Pharma

125

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“…In fact, Crane and Smeets (1974) found that moderate and severe T.D. were detected only in persons who had received a minimum of 14 g of chlorpromazine equivalent with a maximum daily dose of 72 mg. Kennedy et al (1971) worked the dosage and T.D. correlation by analys ing the relationship of the cluster of symptoms with the dosage.…”

Section: Etiological Factors Medicationmentioning

confidence: 99%

Drug Induced Dyskinesia: A Critical Review

Ananth¹

1979

Int Pharmacopsychiatry

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Tardive dyskinesia (TD) has been reported to occur after the long term administration of neuroleptics. Its prevalence has been reported to vary from 0.5-56%. However, no clear relationship is established between a particular neuroleptic, its dosage and duration of administration and the diagnosis and occurrence of TD. Neuropathological investigations have not provided any definitive lessons. In addition, TD can be produced by a number of drugs of different chemical classes. Similarly, the evidence for dopaminergic hypersensitivity is equivocal. The only definitive feature seems to be an individual predisposition, the nature of which needs to be elucidated. Of course, basic to any future research into new insights regarding etiology, the fundamental problem of definition and identification based on the accepted definition are most essential. This solid foundation is necessary for the resolution of any conflicting results that may be reported in the future.

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Extrapyramidal Disorders After Prolonged Phenothiazine Therapy

Cited by 95 publications

References 6 publications

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

Assessment of extrapyramidal disorders.

Drug Induced Dyskinesia: A Critical Review

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