Paradoxical Response to Dopamine Agonists in ...

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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