Metoclopramide in schizophrenia (an open study).
Metoclopramide is a substituted benzamide derivative, which is widely used in the treatment of various gastro-intestinal disorders. Preclinical and clinical studies have shown that metoclopramide possesses appreciable central dopamine blocking properties., It causes hyperprolactinaemia like other available neuroleptics and pretreatment with leavodopa inhibits this prolactin response.
Anti-emetic doses of metoclopramide have been shown to be devoid of antipsychotic therapeutic activity. However, Stanley et al demonstrated in an open study that metoclopramide in high doses has significant antipsychotic activity. Therapeutic doses of metoclopramide, when given intravenously, were found to be useful in the diagnosis of tardive dyskinesia, a condition postulated to be caused by postsynaptic dopamine receptor supersensitivity.
The present study was conducted to evaluate the anti-psychotic and antidyskinetic effects of orally administered metoclopramide.
This study was conducted in the inpatient services of the Departments of Psychiatry and Clinical Pharmacology at K. E. M. Hospital, Bombay.
Male patients ranging in age from 15 to 50 years and satisfying the Research Diagnostic Criteria for acute and subacute schizophrenia were hospitalised for the study. They were rated on the Brief Psychiatric Rating Scale (BPRS) after a one week placebo administration period. Patients whose scores totalled at least 27 points on the BPRS were included in the study. Patients with active schizophrenic symptoms who were already receiving neuroleptic drugs were given a wash-out period of one week and included in the study if they then fulfilled the above mentioned criteria.
Chronic schizophrenic patients with definite signs of tardive dyskinesia were initially rated on the Abnormal Involuntary Movement Scale (AIMS) after diagnosis according to specific criteria. Medication was tapered off over a period of 1 week, and they were evaluated subsequently at weekly intervals on the AIMS for a period of one month. Only those patients whose dyskinetic movements persisted at the end of the one month period were taken up for the study.
Patients with alcoholism, substance abuse, and any clinical or laboratory evidence of systemic disease were excluded from the study.
An informed consent was obtained in all instances.
Metoclopramide was administered orally in a fixed dosage schedule as follows:
1st week: 40 mg t.i.d.
2nd week: 80 mg t.i.d.
3rd week: 120 mg t.i.d.
4th week: Placebo
Evaluations were done initially and at weekly intervals with the BPRS and the Dosage Record and Treatment Emergent Symptoms Scale (DOTES). Chronic schizophrenic patients with tardive dyskinesia were also rated weekly on the AIMS.
A complete haemogram, methaemoglobin estimation, routine biochemical and electro-cardiographic investigations were done initially and at weekly intervals.
Chloral hydrate, trihexiphenidyl and promethazine hydrochloride were the permitted concomitant medications.
The data was analysed, statistically.
Twenty one patients were taken up for the study, from which eleven acute schizophrenic patients and 5 chronic schizophrenic patients with tardive dyskinesia completed the 4 week trial period. Their demographic data is presented in [Table - 1].
Analysis of the total BPRS scores for the group of acute schizophrenics showed a significant reduction in total scores from week 1 to week 3. [Table - 2]. This was maintained at the end of the one week post-treatment placebo period. A significant reduction was obtained in the scores for eight of the eighteen individual BPRS items. This was seen from the 1st week onwards for the items "emotional withdrawal", "suspiciousness" and "blunted affect". The scores for the variables "conceptual disorganization", "depressed mood" and "hallucinatory behaviour" showed a significant reduction from week 2, whereas the scores for the items "somatic concern" and "unusual thought content" showed a significant reduction from week 3 [Table - 2]. When the BPRS variables were ranked according to percentage reduction in mean scores, the variables showing the greatest reduction were "unusual thought content", "suspiciousness", "hallucinatory behaviour", "emotional withdrawal" and "depressed mood" in order of rank. [Table - 3].
Dejonge's test for trend analysis for individual item scores of the BPRS showed a significantly decreasing trend for eight items, namely, "somatic concern", "emotional withdrawal", "conceptual disorganisation", "depressed mood", "suspiciousness", "hallucinatory behaviour", "unusual thought content" and "blunted affect". A significant decreasing trend was also obtained for total BPRS Scores. [Table - 3].
Analysis of the five BPRS factors showed a significant reduction in the mean scores for all factors at the end of three weeks of drug treatment. Significant reduction in mean scores at the end of the post treatment placebo period, was seen for four factors, namely "anxiety-depression", "anergia", "thought disturbances" and "hostile suspiciousness" [Table - 3].
Trend analysis of the mean BPRS factor scores showed a significantly decreasing trend for all factors.
Chronic schizophrenia with tardive dyskinesia:
A similar analysis of both total BPRS scores and the scores for the individual BPRS variables in the group of 5 chronic schizophrenics with tardive dyskinesia did not show significant reduction in scores at any evaluation period. Dejonge's trend analysis did not show a decreasing trend in scores in this group of patients. Analysis of the BPRS factor scores showed no significant reduction in the mean scores and a trend analysis also did not show a significantly decreasing trend in the factor scores.
Analysis of the AIMS scores for dyskinetic movements did not show a significant reduction in either the total scores or in the individual variable scores of the AIMS at any evaluation period [Table - 4].
Dejonge's test for trend analysis showed a significantly decreasing trend from week 1 to week 3 for the total AIMS scores, and in the scores for the following variables: "lips and peri-oral areas", "jaws", "tongue", "upper extremities" and "global severity". [Table - 4].
The DOTES was used to assess the incidence and severity of treatment-emergent symptoms and their relationship with the dose of metoclopramide at a point in time. A total of 154 symptoms were reported by patients from both the groups. Forty five symptoms were part of the initial psychopathology as they were reported to be present on day O. [Table - 5].
Analysis of the remaining 109 symptoms showed that 96 symptoms (88%) were judged by the rater to bear no relationship to metoclopramide as they were part of the initial psychopathology. Twelve symptoms (11%) were judged to the true treatment emergent symptoms. All symptoms were of mild to moderate severity [Table - 6].
All laboratory investigations were within normal limits throughout the study.
The results showed that metoclopramide produced an overall improvement in acute schizophrenic symptoms.
The individual BPRS variables "unusual thought content", "suspiciousness", "hallucinatory behaviour", "emotional withdrawal" and "depressed mood" showed the largest percentage reduction in mean scores. Metoclopramide may possibly have an incisive anti-psychotic action similar to trifluoperazine rather than a sedative action like chlorpromazine.
No improvement in the clinical symptoms in chronic schizopphrenic patients was seen after drug administration. The total number of treated patients was small in this group (n=5). The baseline scores for the BPRS variables "suspiciousness", "hallucinatory behaviour", "depressed mood" and "unusual thought content" were low to begin with and the magnitude of change in these variables was also minimal. The BPRS is not a sensitive measure for rating chronic schizophrenic psychopathology.,
There was an appreciable improvement in the severity of the dyskinetic movements. The greatest percentage reduction in movements was seen in the lips and perioral areas, jaw, tongue and upper extremeties, in order of rank. A significantly decreasing trend in movement scores was obtained at the end of three weeks of drug treatment. Continuing administration of metoclopramide to a larger number of patients for a longer period of time may have produced better results.
Side-effects reported by patients may be due to the primary disease process, to the trial drug, to adjuvant medication or may occur independently. Ayd (as quoted by Klett) has listed a number of symptoms of depression, most of which have appeared on treatment-emergent symptoms checklists. It thus becomes important to establish a relationship between a side effect, its severity and the trial drug. In the present study, analysis of the DOTES showed that extra-pyramidal reactions were the commonest treatment emergent symptom, and these could be easily controlled.
It can be concluded that metoclopramide administered orally in doses ranging from 120 to 360 mg/day had appreciable antipsychotic and antidyskinetic proporties when studied under open non-blind conditions. Extra-pyramidal reactions were the commonest treatment emergent symptoms.
The authors thank the Dean, Seth G. S. Medical College and K. E. M. Hospital for permission to conduct and publish this study. Grateful acknowledgement is made to Ipca Laboratories Pvt. Ltd. for generous supply of the drug.