Use of metoclopramide in the differential diagnosis of drug-induced involuntary movements.
The prevalence of tardive dyskinesia is reported in the literature to vary from less than 10 to more than 50%. An important reason for this widely varying prevalence could be that tardive dyskinetic movements have to be differentiated from other conditions in which similar involuntary movements may be present.
Tardive dyskinetic movements are thought to develop as a result of dopaminergic receptor increase or hypersensitivity following prolonged receptor blockade after chronic neuroleptic drug administration. Metoclopramide a benzamide derivative, is a potent dopamine receptor antagonist. This study describes the usefulness of metoclopramide in the diagnosis of drug-induced involuntary movements.
This study was conducted in the inpatient services of the Departments of Psychiatry and Pharmacology, King Edward Memorial Hospital, Bombay.
A total number of 14 patients were included in the study. [Table - 1] shows the diagnostic breakdown of the study sample.
The following criteria for diagnosis of tardive dyskinesia were used:
(1) Involuntary movements involving the buccal, lingual and masticatory areas.
(2) At least 3 months of neuroleptic medication.
(3) Non-responsiveness and aggravation by anti-Parkinsonian drugs.
(4) Suppression by voluntary effort.
(5) Aggravation by stress or movements in distant parts of the body.
(6) Disappearance during sleep, and
(7) Absence of other neurological or systemic disease.
On entering the trial a physical examination was done to exclude any illness which may vitiate the results of the study, or which may give rise to complications because of drug administration procedure. Each patient received 20 mg or 40 mg of metoclopramide intravenously, or a placebo. The active drug and/or placebo were administered on different days in a randomised fashion. Patients were rated independently by two raters on the Abnormal Involuntary Movement Scale (A.I.M.S.) for severity of involuntary movements. All ratings were done (a) prior to drug administration, (b) ½ hour after drug administration, (c) 4 hours after drug administration and (d) 24 hours after drug administration. Double blind conditions were maintained throughout the trial.
The Pearson Correlation Coefficient for inter-rater reliability between the two raters was 0.984 for severity ratings.
Within group comparisons showed significant reduction in scores from base-line evaluation as compared to evaluation at 4 hours for area 2 (lips and peri-oral area) and area 4 (tongue) for the tardive dyskinetic group under I.V. metoclopramide 40 mg. Significant reduction in total scores was also seen at the ½ hourly and 4 hourly evaluation periods as compared to baseline scores for the tardive dyskinetic group under similar conditions [Table - 2].
Between group comparisons showed significant preference for the tardive dyskinetic group as compared to the non-tardive involuntary movement group for area 2 (lips and peri-oral area) and area 4 (tongue) at the 4 hour evaluation period under I.V. metoclopramide 40 mg. Between group comparisons for total scores also showed significant preference for the tardive dyskinetic group as compared to the non-tardive involuntary movement group at the 4 hour evaluation period under similar conditions [Table - 2].
[Fig. 1] shows the mean A.I.M.S. scores of T patients diagnosed as tardive dyskinesia on the ordinate of the graph, when plotted against time at ½ hour, 4 hour and 24 hour intervals on the abcissa. All patients were administered either a placebo, or 20 mg metoclopramide I.V., or 40 mg metoclopramide I.V. on different occasions, in a double-blind randomised fashion. On metoclopramide 40 mg I.V., there was a significant reduction in scores at 4 hours which showed an increase almost upto base-line level at the end of 24 hours. This is not seen when the graphs showing the response to placebo and to 20 mg IN. metoclopramide are compared.
This is shown more clearly in [Fig. 2], which demonstrates the mean response to metoclopramide 40 mg when administered intravenously to the tardive dyskinesit group and also to the group which had non-tardive involuntary movements.
[Fig. 3] shows an observation on a patient who had Parkinsonian involuntary movements of 2 years' duration. With 40 mg metoclopramide, his score on the AIMS scale increased after half an hour, indicating a worsening in his condition but not at subsequent periods.
The genesis of tardive dyskinesia is obscure; its prevalence rate is not precisely known, its clinical manifestations are varying, its prognosis is uncertain, and its treatment can best be described as 'hopeful'. However, two observations seem to be readily and universally accepted, viz.: that it is probably related to neuroleptic medication, and that hypersensitivity mechanisms may be playing an important part in its causation.
Neuroleptic drugs block dopamine activity by blocking the dopamine receptors in the mesolimbic areas producing a reduction in schizophrenic symptoms, and also in the nigro-striatal areas producing pseudo-Parkinsonism. Prolonged administration of neuroleptic drugs presumably produces a chemical denervation of the receptors. To compensate for this, the post-synaptic dopaminergic neurons in the nigro-striatal areas increase the number of dopamine receptors. A state of dopamine hyperactivity results when the neuroleptic drug-induced blockade of the nigro-striatal dopamine receptors loses its effectiveness either as a consequence of drug withdrawal, or dose reduction, or development of tolerance. The end result is the development of tardive dyskinesias.
The differential diagnosis of tardive dyskinesit movements include schizophrenic stereotypies, involuntary movements associated with various neurological disorders and dyskinesias induced by other drugs.
Metoclopramide is a benzamide derivative which is similar to the powerful antipsychotic agent sulpiride. Its pre-clinical data suggest that it has potent dopamine antagonist properties, it elevates serum prolactin and induces extra-pyramidal side effects like other neuroleptic drugs.
Kababian and Calne have shown that nigrostriatal receptors are not homogenous and uniform, but can be divided into two types viz. Dl and D2. Most of the available antipsychotics are antagonists of both Dl and D2 receptors. Metoclopramide and sulpiride are selective D2 antagonists. This indicates that the effects of metoclopramide on tardive dyskinesia secondary to neuroleptic medication, are worth assessing.
Metoclopramide when administered intravenously in doses of 20 mg in a double blind fashion failed to differentiate between tardive dyskinesia and other involuntary movements. When the dose was increased to 40 mg, it successfully differentiated between these two groups of movement disorders, the maximum reduction being seen in movements of the lips, tongue, and peri-oral areas.
It has been postulated that there may be opposing disturbances in balance between the dopamine and acetylcholine systems in the nigrostriatal areas in parkinsonism and in tardive dyskinesia. The response of our patient with Parkinson's disease to metoclopramide does not seem to bear this out. This may perhaps indicate that the theory of opposing biochemical imbalance between parkinsonism and tardive dyskinesia cannot be applied in all instances. There may be more than one theoretical biochemical basis for tardive dyskinesia, or metoclopramide inspite of its potent dopamine blocking actions, may be working in different ways in Parkinson's disease and in tardive dyskinasia. Preliminary trials have indicated that it does not increase 1-dopa induced dyskinesia or parkinsonian symptoms in patients with Parkinson's disease.
The authors are thankful to Dr. C. K. Deshpande, Dean, Seth G.S. Medical College and K.E.M. Hospital for permission to conduct the project and to publish the report. Grateful acknowledgement is due to Dr. Richard J. Wyatt, Chief, Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Programme, N.I.M.H., St. Elizabeth's Hospital, Washington, D.C. USA, for his help.