J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.941 on 1 August 1974. Downloaded from Journial of Neurology, Neurosurgery, alid Psychiatry, 1974, 27, 941-947 Effect of cholinergic and anticholinergic agents on tardive dyskinesia' H. L. KLAWANS2 AND R. RUBOVITS Fr-om the Divisioni of Neurology, Michael Reese Medical Center, Chicago, Illinois anid the Departmentt ofPsychiatry, University of Maryland, Baltimore, Maryland, U.S.A. SYNOPSIS Tardive dyskinesia, like several other choreiform disorders, is felt to be primarily related to dopaminergic activity within the striatum. Physostigmine has been demonstrated to improve the abnormal movements in patients with tardive dyskinesia while scopolamine tends to aggravate abnormal movements and in some cases elicits abnormal movement not previously observed. This evidence supports the hypothesis that anticholinergic therapy in patients prone to develop tardive dyskinesia may increase the incidence of this disorder the threshold for the by lowering appearance guest. Protected by copyright. of these movements. Tardive dyskinesia is a well-recognized side- been fully elucidated. However, there is evidence effect of long-term neuroleptic therapy (Crane, which suggests that dopamine acting at striatal 1968). The most prominent manifestation dopaminergic receptor sites may be closely is lingual-facial-buccal dyskinesia. Limb and related to the initiation of these choreiform trunkal chorea may accompany the facial move- movements in several clinical settings. Drugs ments (Paulson, 1968). The syndrome is most which alter the availability of dopamine at often seen in patients ranging in age from 50 to dopaminergic receptor sites alter choreiform 70 years who are most often diagnosed as symptomatology. Huntington's chorea is re- suffering chronic deteriorating schizophrenia. lieved by drugs which decrease the activity of Tardive dyskinesia occurs late in the course of dopamine at striatal dopamine receptors, while neuroleptic therapy, often after a decrease in the L-dopa, which markedly increases available drug dosage or discontinuation of the therapy. dopamine, exacerbates the symptomatology of The involuntary facial movements often persist Huntington's chorea (Klawans, 1970, 1973a). for months to years after the neuroleptic treat- L-dopa-induced dyskinesias are also related to ment is discontinued, and the response to any the activity of dopamine at dopaminergic http://jnnp.bmj.com/ type of therapy is poor (Crane, 1968; Delay and receptors in the striatum. It has been suggested Deniker, 1969; Faurbye, 1970). that the prolonged dopaminergic denervation of The lingual-facial-buccal masticatory syn- the striatum characteristic of Parkinson's disease drome is not unique to tardive dyskinesia. The may induce cellular changes that produce a type syndrome was first noted as an integral part of of dopaminergic denervation hypersensitivity the hyperkinesia of Huntington's chorea (Hun- which is related to the appearance of L-dopa-in- tington, 1872). It occurs also as a side-effect of duced lingual-facial-buccal dyskinesia (Klawans on September 23, 2021 by the long-term, high dose L-dopa therapy of et al., 1970). Parkinson's disease (Cotzias et al., 1967). Tardive dyskinesia is also thought to be related The pathophysiology and pathogenesis of to dopaminergic mechanisms. The neuroleptic lingual-facial-buccal dyskinesias have not yet agents which are felt to be responsible for the production of tardive dyskinesia are known to This work was supported in part by a grant from the United block the access of dopamine to striatal dopa- Parkinson Foundation, Chicago, Illinois, U.S.A. 2 Address for reprints: Harold L. Klawans, Division of Neurology, minergic receptor sites (van Rossum, 1967) and, Michael Reese Medical Center, Chicago, Illinois 60616, U.S.A. as a result, produce the symptoms of Parkinson- 941 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.941 on 1 August 1974. Downloaded from 942 H. L. Klawans and R. Rubovits ism (Klawans, 1968). It has been proposed that TABLE 1 the neuroleptic blockade of dopamine receptors DATA ON SUBJECTS STUDIED may be the equivalent of a 'chemical denerva- Sub- Age Sex Diagnosis Dura- Manifestation tion' of those dopamine-sensitive cells (Klawans, ject (yr) tion 1973b). This chemical denervation may, in a (yr) fashion analogous to the pathological anatomical 1 4.7 F SCZ 4 LFB denervation of idiopathic Parkinson's disease, 2 61 F SCZ 6 LFB 3 39 M SCZ 3 LFB+UE+LE induce alterations in the dopamine-sensitive 4 46 F SCZ 7 LFB + UE cells such that, when dopamine access is restored 5 58 M SCZ 9 LFB + LE + trunk 6 63 M SCZ 4 LFB by the diminution or removal of the chemical 1 71 F CBS with para- 6 LFB+UE+LE noid features barrier, an abnormal cellular responsiveness to 8 68 M CBS 3 LFB + UE the dopamine results in the abnormal clinical 9 48 F SCZ 4 LFB + trunk 10 56 F SCZ 6 LFB features of lingual-facial-buccal dyskinesia 11 52 M Chronic anxiety 9 LFB+UE+LE+trunk (Rubovits and Klawans, 1972; Klawans, 1973b). 12 61 F Chronic anxiety 8 LFB+ UE Although the pathophysiology of lingual- seems most SCZ: Schizophrenia. CBS: Chronic brain syndrome. LFB: Lingual- facial-buccal dyskinesias to be facial-buccal dyskinesia. UE: Upper extremity choreatic movement. closely related to dopaminergic mechanisms in LE: Lower extremity choreatic movement. the striatum, other neuronal systems, particu- larly cholinergic pathways, also influence striatal guest. Protected by copyright. function. Acetylcholine has been shown to The striatal cells, as a result of pro- exert an influence on the striatum opposite to gic receptors. denervation, may be over or that of dopamine, and a balance of influence of longed chemical to Thus a two neurotransmitters on the striatum is abnormally responsive dopamine. the between the cholinergic thought to be necessary for normal function functional imbalance Since acetylcholine and and dopaminergic systems is established. This (Klawans, 1968, 1973a). the influence dopamine have opposite effects on the striatum study was undertaken to investigate and anticholinergic agents in and a balance is necessary for normal striatal of cholinergic is reasonable that manipulation of patients with tardive dyskinesias. It was pre- function, it chorea, choliner- the effect of one system would modify the effect dicted that, as in Huntington's That manipulation of the choliner- gic agents would tend to restore the functional of the other. and alleviate gic system can alter the symptomatology of balance of the neurotransmitters diseases in which the pathophysiology relates the symptoms and that anticholinergic agents most directly to dopaminergic mechanisms has would worsen the abnormal movements. been demonstrated in Parkinson's disease and Huntington's chorea. METHODS It is most significant that cholinergic and anti- The subjects included in this study were 12 patients http://jnnp.bmj.com/ cholinergic agents have been shown to modify clinically diagnosed as having tardive dyskinesia the hyperkinesias of Huntington's chorea (Table 1). The patients had been treated with neuro- (Klawans and Rubovits, 1972). Physostigmine leptic agents for three to nine years, with an average which increases the levels of acetylcholine avail- of 5-75 years of therapy. Seven subjects were female, able to act upon the striatum relieves choreiform five were male, ranging in age from 39 to 71, with an symptoms while benztropine, an anticholinergic average of 55-8 years. The average ages and dura- tions of neuroleptic therapy did not differ between agent, intensifies choreiform symptomatology. It on September 23, 2021 by had been appears then that manipulation ofthe cholinergic the sexes in our sample. Eight patients diagnosed as chronic schizophrenics, two as having a system significantly influences the symptomatol- chronic brain syndrome, and two as having chronic ogy of the choreatic movements in a disease anxiety. In all subjects, lingual-facial-buccal dys- (Huntington's chorea) in which the underlying kinesias were the most prominent manifestation of pathophysiology seems to be more directly tardive dyskinesia; in three cases it was the only related to dopaminergic mechanisms. Tardive symptom. The remaining nine cases demonstrated dyskinesia is thought to be related to an abnor- limb chorea and/or trunkal movement abnormalities mal influence ofdopamine on striatal dopaminer- in addition to the lingual-facial-buccal dyskinesias J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.8.941 on 1 August 1974. Downloaded from Effect of cholinergic and anzticholinergic agents on tardive dyskinesia 943 TABLE 2 the inner border of the lower lips was recorded. The EFFECT OF DRUGS ON DURATION OF TONGUE EXTENSION trial was stopped arbitrarily at 30 seconds. This ability was measured at least twice per session, each Drug Number Duration of tongue extension measurement being preceded by a rest period of 30 tested Before After seconds. All numbers represent the average of at (s) (s) least two trials. The difference between trials was six seconds or Physostigmine 12 11-4 23-4 P< 0 05 always less. (range 4-28) (range 11-30) DRAWING The ability of each patient to draw Edrophonium 4 13-9 12 1 (range 6-20) (range 4-18) Archimedes' screw was periodically observed. Scopolamine 4 18 4 6-3 P<0 05 (range 16-30) (range 3-15) RESULTS EFFECT OF PHYSOSTIGMINE The length of time the patient could keep his tongue protruded was increased by physostigmine in 10 out of 12 (Table 1). Eight patients were receiving neuroleptic As shown in medication when tested in patients. Table 2 the average dura- this study, four (cases 5, 8, tion of tongue extension was increased signifi- 11, and 12) were not. At the time they were studied none of the patients had drug-induced Parkinsonism. cantly by physostigmine, from a pretreatment Each patient was informed as to the nature of the average of 114 seconds (range 4-28 seconds) to guest. Protected by copyright. two agents to be used, physostigmine and scopol- 23-4 seconds (range 11-30 seconds) after 30 amine, and the possible side-effects.