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W Greil, H Haag, G Rossnagl and E RÖºther
Effect of anticholinergics on tardive dyskinesia. A controlled
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British Journal of Psychiatry(1984), 145, 304â€”310
Effect of Anticholinergics
A Controlled Discontinuation
W. GREIL,H.HAAG,G.ROSSNAGLand E.RUTHER
phrenic patients with pronounced symptoms of tardive dyskinesia (TD)were
withdrawn from anticholinergic medication. All patients had previously been
under long-term treatment with neuroleptics and anticholinergics for at least
two years. The rating-scalesused were the AIMS, our own TD Scale, and the
Simpson-Angus scale for extra-pyramidal side-effects. The severity of TD
c@@creasedsignificantly in nine patients within two weeks; this improvement,
most pronounced in the oral region (P <.001), persisted during a six-week
placebo period. There was a slight increase in parkinsonian
which was not a prerequisite for improvement in TD.Hence,discontinuation of
anticholinergic medication is a possible therapeutic approach in patients with
In a double-blind, placebo-controlled study, ten chronic schizo
two years or more.
seen in the oral region (e.g. tongue protrusion
rocking) and of the extremities
movements' of the fingers, or â€˜¿?stamping movements'
ganglia. Accordingto this hypothesis,
cholinergicactivity,as seen in case reports
DiMascio,1977; Weiss et al, 1980; Kiloh et al, 1973).
Again, this assumption is strongly supported by both
uncontrolled(Fann & Lake,
(Gerlach& Thorsen,1976) studies.
Less attentionhas been paid to the question
happens to TD when anticholinergics
drawal studies, Burnett (1980) and Reunanen (1982)
usually not observed
is a side-effectof late onset
it is characterised
In additon,many of the TD
of the trunk
of a hypothetical
system in the basal
of TD by weakening
can be expectedto
In two previouswith
thirteen patients respectively.
study illustrate the clinical relevance of the relation
ship between anticholinergic
of 814 patients,52% received
with anticholinergic medication in addition to neuro
cholinergic drugs was higher amongst TD patients than
The aim of the present study was to investigate
effect of withdrawalof anticholinergic
after their long-term administration.
of anticholinergicsdrugs in ten and
in an unpublishedepiderniological
drugs and TD. In a group
drugs on TD,
Patients and Methods
as chronicschizophrenics(ICDâ€”9 Classification
Disorders), were selected for this study; Table I gives their
main characteristics. Their ages ranged from 35 to 65 years
Selection criteria required that patients:
1. Had received long-term maintenance treatment with
years, the dosage having remained
2.Had significant i'D (a total severity score of at least 3,
according to AIMS).
EFFECT OF ANTICHOLINERGICS ON TARDIVE DYSKINESIA
BEN = benperidol, THIO = thioridazine, FLUPH = fluphenazine,
PER =perphenazine, FLUPE = fiupenthixol,HAL =haloperidol.
Localisation of TD-symptoms
Number of patients
3.Had manifested TD for at least one year, and that the
severity of the symptoms had been stable for at least one
month before admission to the study.
All patients with severe physical illness, neurological
disease or alcoholism/drug dependence were excluded from
o 1234 56
ft t ftftt t
Time schedule for clinical examinations.
The diagnosis of tardive dyskinesia was based on the
presence of a â€˜¿?typical'bucco-linguo-masticatory
(BLM syndrome,i.e. movements
and the jaw of the tongue
7.64 Â± 1.41
5.42 Â± 1.7918.24
12.28 Â± 18.51
3.93 Â± 1.83.001
2.66 Â± 2.69
2.99 Â± 0.94
2.46 Â± 0.98.005
W. GREIL, H. HAAG, G. ROSSNAGLAND E. RUTHER
and perioral dyskinesias) and the absence of other adequate
explanations for the movement disorder, such as Hunting
ton'schorea,Wilson's disease or other
In addition to the BLM syndrome, all patients showed
dyskinesias of the trunk or extremities (see Table II).
The study was carried out double-blind, placebo-controlled
and the investigators were not informed about the study
design. The ten patientschosen
two groups: Group A (n = 4) and group B (n = 6). Patients of
group A received biperiden for four weeks in the same dosage
as prior to the study, followed by a three-week placebo
period.Patientsin GroupB remained
week, and were then switched to placebo for six weeks.
were carried out weekly through the study (Figure 1). All
patients were ratedon biperiden and on placebo at least three
The dosage of neuroleptic medication remained unchanged
during the study.
After the seven-week study period, each patient's doctor
decided whether or not to reinstitute anticholinergic treat
ment and all patients were re-examined twice during the
following month under non-blind conditions.
Allexaminationsof indi@'idual patientswerecarriedout at
the same time ofday, mainly during the late morning. Ratings
were done simultaneously by the two investigators (OR,
HH), the scoresrepresentingthe averageofboth.
Following each session, the investigators completed the
Simpson-Angus scale (Simpson & Angus, 1970) for pseudo
parkinsonism, the AIMS (Guy, 1976), and our own addi
tional TD scale constructed on the lines laid down by Gerlach
(1976),Simpson(1979) and Heinrich
scale was designed to assess the individual TD symptoms in
The definitionof symptoms
derived mainly from the TD scale developed by Simpson
The scoring used in this study scale was taken from the
Gerlach scale.The individualTD symptomswere described
with regard to their frequency and amplitude, both graduated
from 0 to 6. The sum of these two scores was then multiplied
by an intensity factor (Gerlach & Thorsen, 1976), based on
the following system: multiply constant movement by three;
multiply intermittent movement by two (i.e. present more
than half of the observation period), and no multiplication for
occasionalmovements (i.e. present
The total severity of TD was evaluated
functional difficulties (e.g. difficulties in swallowing, in
impairment of subtle finger movements or in walking) and
psychosocial impairment (i.e.
The total score on the Simpson-Angusscaleisgivenhere
without dividing it by ten, as originally described by Simpson.
For statistical analysis, the mean values of the three weekly
ratings preceding discontinuation
pared to the three ratings following its discontinuation (t-test
for paired differences). Pearson's correlation coefficient was
calculated for the relationship between pseudo-parkinsonism
were randomly assignedto
on biperidenfor one
(1968).Our own TD
in our own study scale were
less than half the period
in terms of
of biperiden were com
Global evaluation of TD under biperiden (mean value of
three ratings before discontinuation)
value of three ratingsafter discontinuationof biperiden) on
the basis of the study scale and the AIMS;
â€˜¿?Thefour scores of the study scale and of the AIMS were
highly correlated (PEARSON'
betweenr = .86andr = .90)
and placebo (mean
n = 10; t-test for
The changes in the mental
according to the total clinical impression without using
psychopathological rating scales.
state were documented
Nine patients completed the trial. One patient (number 10,
group B) dropped out one week after biperiden withdrawal
because of severe parkinsonism; in this patient, only one
rating could be carried out while on the placebo.
Total assessment of TD
The effect of the discontinuation of biperiden on TD is
shown in Table III. The switch to placebo resulted in a
considerable improvement of the BLM syndrome and in a less
The BLM syndrome(study scale) improvedfrom 33.8 Â±
7.7 on biperiden to 18.2 Â±10.2 on placebo (P <.001), while
the total scoreof trunk and extremitymovementsimproved
from 28.9 Â± 22.8 to 12.3 Â± 18.5 (P <.10).
Frequency, amplitude, and the intensityfactor (the three
(P <.01), and functional impairment was reduced as well,
althoughto a somewhat lesser extent.
Â± 8.871.60Â± 1.89â€”
EFFECT OF ANTICHOLINERGICS ON TARDIVE DYSKINESIA
rose from 17.9 Â±6.9 on placebo to 34.3 Â±19.0 on the
reintroduction of biperiden.
The remaining five patients who were not prescribed
anticholinergic drugs again showed a further improvement of
the BLM syndrome; the mean value for these patients
decreased from 18.5 Â± 13.7 on placebo to 14.9 Â± 12.2 in the
3). The meanvalue (forthe fivepatients)
Individual TD symptoms
Table IV gives an overview of the changes of the TD
symptoms indifferent topographic regions. Only four of these
symptomswere present in a sufficientnumber of patients to
permit statistical analysis.
The most pronounced improvement after biperiden was
<.0001). In the five patients who were again prescribed
biperiden after the end of the study, the mean values rose
from7.4 Â± 3.4 to 14.0Â± 7.2 (tongue movements)and from
6.9 Â± 2.2 to 13.4Â± 5.1 (jaw movements),respectively.The
improvement of the remaining fivepatients who were not
prescribed biperiden again, persisted during the follow-up
period;themeanvaluesdecreasedfrom8.2 Â± 6.7to7.0Â± 6.0
(tongue movements) and from 7.5 Â± 4.7 to 5.4 Â± 6.2 (jaw
A clear-cut improvement was also observed with regard to
rotation/fiexion movements of the ankles (n = 7; P <.01).
The dyskinetic movements of the fingers exhibited only an
insignificantreductionon placebo(P <.20). For the remain
ing symptoms, conclusions can hardly be drawn because of
the small number of patients involved. Perioral dyskinesias
and dyskinesias of the toes and the hip seemed to improve
under placebo; arm and wrist movements showed no
FIG. 2â€”Changesof the BLM-syndrome during the 7-week
study-period in group A (n = 4) and in group B (n = 6 in
weeks â€”¿?1+1; â€”¿?1 to +1;n = Sin weeks +1 to7).
FIG. 3â€”BLM-syndrome under biperiden (mean scores of
three ratings before discontinuation)
scores of three ratings afterdiscontinuation
n = 10.
Broken rules: BLM-syndrome in 5 patients on biperiden
again (mean scores of the follow-up examinations).
and placebo (mean
essentially the same, with the exception of a significant
reduction(P <.01) oftrunk andextremitymovements.
on the basis of the AIMS (TableIII) were
Course of tEl-improvement
In both group A and group B, the improvement in i'D
occurred within the first two weeks after biperiden with
drawal (Figure 2). This improvement persisted, as could be
seen in group B during a six-week placebo period.
After the end of the study, biperiden was reintroduced in
five of the ten patients. Within one month, four of these
patients showed a pronounceddeterioration of the BLM
TD-symptoms in different topographic regions under
n = number of patients.
W. GREIL, H. HAAG, G. RQSSNAGLAND E. RUTHER
documented on our own study scale and on the AIMS.
The reduction ofTD seemed to be more pronounced
in relation to the oral dyskinesias than the limb and
trunk movements, but this finding may reflect rating
problems rather than a real difference.
of oral dyskinesia can be worked out more easily, and
they seem to be less masked by voluntary movements
than are limb and trunk dyskinesias.
It could be argued that in therapeutic studies of TD,
there is a generaltrend towards
ably due to selectionof patients
towards a favourable outcome. The severity of TI)
the selection of patients with pronounced symptoms,
the probability of choosing an individual patient with
maximum symptomsis much larger than that of one
with minimum symptoms.This results in some statisti
cal expectancy of improvement
regardless of the real efficacy or inefficacy of the tested
In the present study, the improvement
appeared to be clearly related in time to withdrawal of
to placebo (week1) resulted
within one or two weeks,
were at that time still on anticholinergic
then switched to placebo (week 5), patients in group B
showed the same prompt reduction of TD as those in
groupA previously. The average
patients(group A + group B) show a relatively con
stant baseline during the three weeks before discon
tinuation (34.2 Â±10.9; 34.5; 12.2; 33.8 Â±11.1); the
scores in the three weeks after discontinuation
15.3; 11.8 Â±5.9 Â±18.3 Â±14.5) are all significantly
lower than the baselinevalues
P <.05, compared to the last baseline value).
There are three possible explanations
of withdrawal of anticholinergic
plasmalevels of neuroleptics
influence the severity of TD.
cally suppressedby an aggravation
3.Improvement of TD might be due to an increase in
central cholinergic activity.
As for the relationship
neuroleptics and anticholinergic
nite conclusionscan be drawn from previous investiga
tions. An increase was found by Kolakowska et a!
(1976), a reduction by Morselli eta! (1980); Gautier et
a! (1977); and Rivera-Calimlim
in group A the switch
in a reduction
patients in group
of TD. When they were
BLM scores of all
(P <.025; P <.005;
for the effect
and thus indirectly
might be mechani
of rigidity after
betweenplasma levels of
(1976) and no change
induced by the switch from
biperiden to placebo (â€”p).
The switch from biperiden
scale) of pseudo-parkinsonism in three out of the ten patients;
the mean values for all patients increased from 1.3 Â±1.2 on
biperidento 2.7 Â±2.4 on placebo
had to be omittedfromthe study
severe pseudo-parkinsonism,in the shape mainly of tremors,
in the same topographicalregion in which she had exhibited
There was no relevantrelationship
The most impressive improvement
patientswho did not develop
improvementof TD.No significant
could be found between the severity of pseudo-parkinsonism
and the severity of the BLM syndrome (Pearson's correlation
coefficient;r = â€”¿?.22; n.s.).
to placebo resulted in an
two pointson the Simpson-Angusthan
of TD (Figure 4).
was found in four
with the greatest
only a comparatively
In seven patients, a worseningof their mentalstate was
noted during the study period. In fivecases, the deterioration
seemedto be relatedin time to withdrawal
In ten patients with tardive dyskinesia
1982), withdrawalof anticholinergic
who had been
et al, 1980; Reunanenet a!,
led to medication
severity of theof TD,as
EFFECT OF ANTICHOLINERGICS ON TARDIVE DYSKINESIA
Linnoila et al(1980);
of neuroleptics induced by anticholinergics, they are
not likely to be markedenough to produce
Hence, thebest explanation
withdrawal of anticholinergic
tion of TDby inducing
The number of patients in the present study is too
small to analyse statistically
individualTD symptoms to withdrawal
ergic drugs.However, to sum up the findings of this
and previous studies(Hippius
Klawans & Rubovits, 1974; Sovner & DiMascio,
Fann & Lake, 1974b) the following
be classified as â€˜¿?dopaminergic'movements,
sense that they are aggravated
anticholinergic, and improved
and cholinergicagents: Dyskinesias
tion/flexionmovements of the ankles,
the toes, and hip-rocking.
of the dyskinetic arm and leg movements
ergic drugs(Gerlachet a!, 1974; Casey
1977; Moore& Bowers,
appears to be distinctfrom
Apart from their therapeutic
to have additional psychotropic
study,deteriorationof the mental
anxiety) in five patients seemed to be related in time to
is based only on case records however,
fact mustbe takeninto consideration
of anticholinergictherapy can be interpreted,
least,as a reactionto increased
Forsman& Ohman (1979),Itohet a!(1980);
and Simpson et a! (1980).
even if there are changes in plasma levels
of TD by rigidity)
was no correlation
seems tobe that
drugs leads to a reduc
a change in the central
& Logemann, 1970;
of the tongue and
of the fingers,
(of a more
but this syndrome
drugs are thought
1982). In the present
drugs. This assumption
and no relevant
in part at
which is more troublesome
previousTD. In the present
be put back on anticholinergic
treatment of the individual
is least impaired
of TI) by anticholinergic
to the patient
study, only a few weeks
five out ofthe ten patients had to
the other five patients,
patient with TD so that he
should be to try to discontinue
to an extent
than was the
We would like to thank the staff of the Bezirkskrankenhaus
Haar in which the study was conducted. Our thanks also to
Knoll AG for supplying the placebo.
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(Received 8 November; revised 27 December1983)