Paradoxical. Response to Dopamine. Agonists in Tardive. Am J Psychiatry. 134:7, July 1977. 785. Dyskinesia. BY BERNARD. J. CARROLL,. M.B.,B.S.,. PH.D.,.
Paradoxical Dyskinesia
Response
BY BERNARD J. CARROLL, AND EMRE KOKMEN, M.D.
to
M.B.,B.S.,
Dopamine
Agonists
PH.D.,
C. CURTIS,
GEORGE
The authors conducted an extensive pharmacological analysis ofa patient severely affected by tardive dyskinesia. No drug treatment gave lasting clinical improvement. Several agents recently recommended for this condition, dimethyl aminoethanol, clozapine, and thioridazine, failed to modify the dyskinesia. Reserpine caused a worsening ofthe symptoms. A paradoxical and unexpected improvement was observed with apomorphine injections and with lowdosage oral L-dopa. These two drugs may have acted by stimulating
presynaptic
inhibitory
lesion
NEUROCHEMICAL
A
heterogeneity
of
disease
to control
the
several unsuccessful given experimentally Revised
version
the Amencan 14. 1976. Drs.
Carroll
Psychiatry is Assistant versity of
of a paper
Psychiatric and Curtis
abnormal
clinical so that presented
dyskinesia
Association. are Professors
I 29th
is
Miami
Beach.
of Psychiatry,
and Mental Health Research Institute, Professor of Neurology, Department Michigan Medical Center, Ann Arbor,
Fla.
meeting
of
May
10-
Department
of
and Dr. Kokmen of Neurology, UniMich. 48109.
The authors gratefully acknowledge Martin Kafka, M.D., Barry Carlton, M.D., and Randolph Nesse, M.D., residents in psychiatry, Mary Moriarty, RN. . and Catherine Doherty, R.N. , research nurses, and ward staff for their assistance in the care and study of this patient.
old
next
age
when
she
year
rational
Her
relevant
episode
and
she became
to the NeuMedical
incident
psychiatric
psychotic
treatments
was admitted of Michigan
documented 15.
became
she
more
University
a poorly at
of
psychotic
‘ ‘
subclinical
began
illness
was
Cen-
in her mcdi-
treated
again
at age
with
and
ECT.
received
neuroleptic drugs. Between the ages of 28 and 36 she was hospitalized at least 12 times and received continuous outpatient treatment in the intervals. The details of her drug treatments during this 8-year period are not known cornpletely. There is documentation, however, that at various times she received 800 mg/day of thioridazine, 40 mg/day of and
several months. nesia were noted
has
,
was
when
and
1973. The only
tnifluoperazine,
After
annual
36 years Institute,
history
The
movements.
A was
in February
27,
mechanisms
be observed be provided.
poliomyelitis”
trials other drugs were their effects on the dyskiat the
REPORT
cal
been suggested by some authors who use the highly viriable responses of patients to drug treatments as their major line ofevidence (1). Consequently, there is a need for extensive use of many drugs in individual patients, both to find agents to control the abnormal movements and to provide a pharmacological profile of the disorder. Since the movements are especially variable in patients with mild forms of tandive dyskinesia, severely affected subjects are the most suitable for long-term studies. This report describes the treatment of one such patient, who took 19 different drugs over a period of 2 years. Some of the drugs were used in attempts
CASE
ter,
not well understood, and it has not been established that all patients with the disorder have the same neurotnansmitten defect(s) on will respond to the same drugs.
could then
Ms.
dopamine
in tardive
nesia could
Tardive
M.D.,
ropsychiatric
receptors.
THE
in
movements.
From
neuroleptic worsened. was
400
mg/day
each
chlorpromazine,
for
age
32 to age
36 she
received
intensive
drug treatment, and her dyskinesia For 4 months before her admission
receiving
the
following
day of chlorpromazine, day
of
At age 32 the first symptoms of her dyskiin the form of frequent eye blinking and oral progressively to our unit she simultaneously: 400 mg/ of trifluoperazine, 48 mg/
drugs
40 mg/day
of perphenazine,
and
10 mg/day
At the time ofadmission
of benzhexol.
she was not psychotic.
Her main
psychological complaints were severe anxiety about her deteniorating marriage and distress at her abnormal movements. A careful drug history was not obtained at this time, and the patient was diagnosed as having a hysterical tic, based on the observations that her movements became more severe when she was anxious or under stress and on psychodynamic interpretations of her personal history. During her first 6 months of hospitalization she was treated in psycho-
therapy;
halopenidol
symptoms
became
was
tant observations were be achieved temporarily turned
even
abrupt lowed
given
disabling. made: with
though
the
intermittently
During 1) control haloperidol,
drug
was
when her two impor-
period
ofmovements but they
continued;
could later re-
and
2)
the
discontinuation of haloperidol was sometimes folby the disappearance of the movements for several
days. In August saw the patient.
1973 a new resident Her drug history was
nosis
dyskinesia
of
tardive
The movement muscles,
this
axial
lower
limbs.
spasm
were
disorder muscles
Frequent present;
(neck
and a new consultant obtained and the diag-
was made. involved the patient’s
and trunk),
blinking grotesque
Am J Psychiatry
oral-facial
and both
and spontaneous facial
grimacing
134:7,
July
upper
and
blepharooccurred
1977
to-
785
RESPONSE
TO
DOPAMINE
AGONISTS
gether with rolling tongue movements and lateral movements of the mandible. These oral-facial-lingual movements were complicated by bruxism, leading to the breaking of several teeth and to occasional tongue-biting. Poor oral hygiene, drooling
of saliva,
and
excoriation
of her
skin
around
the
mouth and chin were present. When her oral movements were very severe, she was unable to eat solid food because ofdysphagia. tinuous
As a result
dyskinetic
38.6 kg) and appeared nesia
included
clinical
psychotic,
the
disappeared
pressed
picture
chorea
also
food
intake
weight
(from
Other
features
resembled
(2).
When
movements
during
lost
and con50
kg
to
of her dyski-
head movements, spasm of her cerflexion, opisthotonos, abdominal rimovements of her arms and legs.
ballistic
Huntington’s
she
emaciated.
vical muscles, truncal gidity, and choreoathetoid
The overall
of inadequate
movements
were
sleep.
A became
movements
voluntary
stage anxious
exaggerated;
The
by competing
an advanced
Ms.
they could
activity;
e.g.
of or
always be ,
sup-
all the
facial movements disappeared during forced protrusion of the tongue. Ms. A’s neurological status was otherwise unremarkable except for mild rigidity of all limbs and symmetrically
decreased
limb
tion, including skull pneumoencephalogram,
reflexes. X-ray,
mal results. There was diagnoses of Huntington’s
tonia
musculorum
Further
neurological
EEG, radioisotopic and lumbar puncture
no clinical chorea,
evidence Wilson’s
evaluabrain yielded
scan, nor-
to support the disease, or dys-
deformans.
DRUG
TREATMENTS
Group
1 : Miscellaneous
AND
RESULTS
Sedatives
Ms. A did not improve with any of the following treatments: 90 mg/day of phenobarbital for 21 days, 400 mg/day of amylobanbital for 1 1 days, on 100 mg/ day of diphenhydramine for 10 days. The two banbiturates produced only a decrease of anxiety symptoms without a major decrease in the dyskinetic movements. The effect of the antihistaminic drug was simiIan and did not suggest that central nervous system (CNS) histamine mechanisms might be implicated in the disorder. The f3-adrenergic receptor blocking drug propranolol, which is effective in some extnapyramidal disorders such as familial tremor and lithium-induced tremor (3, 4), did not improve the dyskinesia when given in a dose of 160 mg/day for 8 days. The antidepressant drug desipramine, given for 1 1 days, did not improve or worsen the movements but did precipitate psychotic behavior. The minor tranquilizers diazepam and chlorazepate, given for 14 and 21 days, respectively, had no definite effect on the movements. Group
2: Cholinergic
and Anticholinergic
Agents
Physostigmine salicylate was given intravenously in a dose of I mg 10 minutes after peripheral anticholinengic blockade with 2 mg of scopolamine methyl bromide intravenously. Within 10 minutes the patient developed severe rigidity and increased movements. This reaction was terminated by 2 mg of intravenous atnopine sulfate. Dimethylaminoethanol was given because of reported success in treating some patients with tardive dys786
Am
J Psychiatry
134:7, July 1977
kinesia (5, 6). No clear improvement in the dyskinesia was obtained with a dose ofup to 1500 mg/day oven 19 days. Serious peripheral cholinengic side effects occurred in the form of rhinorrhea, excessive salivation, and bronchorrhea (7). Benztropine, an anticholinergic drug, was given in doses of ‘I-6 mg/day over 2 weeks. This drug caused a doubtful mild improvement in the dyskinesia togethen with a mild organic brain syndrome that cleaned when the drug was stopped. When given in conjunction with haloperidol, benztropine did not improve the duration ofcontrol ofthe dyskinesia observed with halopenidol alone. Group
3: Functional
Antagonists
of Dopamine
Resenpine was given because of previous reports that it and tetnabenazine were effective treatments in some patients (8, 9). At a dose of 2 mg/day for 8 days reserpine caused a marked increase of movements and severe rigidity developed along with hypotension and bradycardia. Thioridazine at a dose of 400 mg/day for 20 days caused no improvement in the symptoms. This drug was used because of reports that tandive dyskinesia rarely occurs in patients receiving thioridazine (10). Clozapine has been reported as dramatically effective in controlling some cases of tardive dyskinesia (11). When given at a dose of up to 1000 mg/day for 18 days, this new neuroleptic did not alter the symptoms. Halopenidol treatment in doses of 20 mg/day produced good control of the dyskinetic symptoms on several occasions. A mild rigidity and parkinsonian facial appearance developed as the abnormal movements abated. This control persisted for 4 to 6 weeks, after which the movements returned at full intensity, despite continuation ofthe halopenidol. When the dose was increased to 30 or 40 mg/day, the movements were controlled again but for only 1-2 weeks before the dyskinesia reappeared. When haloperidol was then discontinued, the movements stopped rapidly within 48 hours, remained absent for 10-14 days, and then reappeared oven a 2- to 3-day period. This sequence of events was documented on three separate occasions; it does not appear to have been described previously in other patients with tandive dyskinesia. Group
4: Dopaminergic
Agonists
Amantadine at 300 mg/day caused no improvement or worsening ofthe dyskinesia when given for 6 days. d-Amphetamine was given once only in an oral dose of 10 mg. It caused an increase of activity and hostility together with a worsening of the dyskinesia. i-Dopa was given in gradually increasing doses oven a period of 21 days. Ratings of the dyskinesia were obtained daily by the ward staff using the Visual Analog (10-cm line) Scale ofGlobal Severity (12). Figure 1 shows that doses between 2 and 4 g/day reduced the severity
days
of
when
the
movements.
the dose
The
was 0-2 g was
mean rating for 12 67.6 (SD= 17.4) com-
CARROLL,
CURTIS,
AND
KOKMEN
FIGURE 1 FIGURE 2 Ratings of Dyskinesia Severity After Two Injections
Ratings of Dyskinesia Severity During Treatment with 1-Dopa
of 4 mgof Apomor-
phine HCI 100
-
80
60
40
20
3k0 0
First apomorphine
60
90
injection
150
Second
MINUTES
6
120
AFTER
180
apomorphine
210
240
injection
MEDICATION
5
injections 4
of apomorphine.
Placebo
injections
did
not
modify the movements. This effect of apomonphine was observed repeatedly. As this was the only effective treatment besides halopenidol, the patient received 2-6 mg of apomorphine subcutaneously every 2-6 hours for 2-4 weeks. Each injection was followed
3 2
by suppression 0 I
t
i
i
I
#{149} i
i
i
5
I
I
i
10
I
i
20
15
DAYS
ON
L
MEDICATION
pared with 42.5 (SD= 19.8) for 12 days at 2-4 g(p
