1369 CONVULSIONS IN PATIENTS ON ANTIDEPRESSANTS
don older and established compounds for newer drugs whose toxic potential has not yet been fully revealed. Animal experiments are unhelpful. Rabbits perfused intravenously with amitriptyline, imipramine, maprotiline, or mianserin5 developed convulsions at different dosages, and, although mianserin was the least toxic in this respect, the doses used were much higher than those used clinically, so the applicability of the experiment to man is questionable. We have, therefore, to rely on epidemiological data. The accuracy and usefulness of reports can be increased if those reporting data on seizures provide more detail, including information on preexisting disorders predisposing to epilepsy, the concomitant use of other potentially epileptogenic drugs, and withdrawal from drugs and or alcohol. I thank the Committee
on
Safety
Royal South Hants Hospital, Southampton, SO9 4PE *Drugs introduced in Britain for depression. t% of prescriptions. Source: Medical Data Index 1979, vol III (Intercontinental Medical Statistics, Harrow, Middlesex). Shares marked.. total less than 1.4% between them. C.S.M. as convulsions deaths shown in parentheses).
treported
to
or
grand-mal
convulsions
(numbers of
of Medicines for
supplying
data.
J. GUY EDWARDS
PLASMA AMINOACID IMBALANCE IN PORTAL-SYSTEMIC ENCEPHALOPATHY
SIR,-Dr James and colleagues (Oct. 13, p. 772) propose a hypothesis for portocaval encephalopathy in which there is a close biochemical relation between portal systemic encephaloepileptogenic potential of antidepressants, but should be interpathy (PSE) and the encephalopathy seen in chronic respirapreted with caution. Only about 10% of adverse reactions are tory failure. Having ourselves noted such a similarity of neuroreported to the C.S.M.,l although this figure could be higher logical symptoms in these disorders, we have been trying to for alarming reactions such as seizures; the percentage of cases find out if they have metabolic abnormalities in common, in reported may also vary with the drug, and clinicians often do respect of plasma aminoacids. not report well-known side-effects of a particular drug. The Patients with chronic respiratory failure were studied durnumber of reactions reported has to be seen in relation not ing a period of acute decompensation accompanied by an enceonly to the quantity of drug prescribed but also to the amount phalopathy. None had signs of hepatic insufficiency. Plasma taken by the patient, and compliance is seldom known accuaminoacids were determined by ion exchange chromatography is difficult to prove for drugs and unrately. Cause-and-effect (T.S.M.1) for fifteen patients before and after the disappearance of neurological signs. We calculated the ratio (R), defined wanted effects.2 as (Val+Leu+Ileu) — (Phe+Tyr), the variations of which I am doing a placebo-controlled study of mianserin and Fischer et al.’ have studied in chronic and acute hepatic encemaprotiline in depressive illness, and was therefore concerned phalopathy (normal range 3-3-5). We found R to be abnorabout reports of epileptic attacks in patients receiving maprotimally low in patients with encephalopathy. R rose significantly line,3.4 and, now, mianserin. I have been collecting background and in parallel with the decrease in P aC02 after the signs of data on patients whose seizures have allegedly been caused by encephalopathy had disappeared (table). Furthermore, there mianserin: in many of them the cause of the seizures seems very uncertain. One mentally subnormal patient who was reported as having had grand-mal attacks while taking mianserin had malignant hypertension and hypertensive retinopathy. His consultant did not think that mianserin was the cause of the attacks, because of the severe hypertension and because the patient had been taking mianserin for 10 months before they occurred. In another case the patient was suspected of having an organic brain disease which itself could have caused the attack. A third patient, an alcoholic, was withdrawing from large dosages of diazepam when the seizure happened. In other instances patients were concurrently receiving other potentially epileptogenic drugs or were being withdrawn from benzodiazepines.
Despite the difficulties in interpretation,
some of the figures The number of seizures reported in patients on amitriptyline and imipramine is small, even though these drugs have been marketed for a long time and have a large share of the market. In contrast, many cases have been associated with maprotiline, a drug that has been marketed in Britain for only a few years. Perhaps we should not readily aban-
call for
comment.
D. The use and abuse of psychotrophic drugs. Scott Med J 1971; 16: 345-49. 2. Edwards JG. Unwanted effects of psychotropic drugs; I. Some general considerations. Practitioner 1977 218: 556-62. 3. Shepherd GAA, Kerr F. Maprotiline hydrochloride and grand-mal seizures. Br Med Jl 1978; 1: 1523. 4. Hall MJ, Russell RI. Maprotiline hydrochloride and grand-mal seizures. Br Med J 1978; ii: 961. 1.
Dunlop
ARTERIAL BLOOD GAS ANALYSES AND R VALUES IN FIFTEEN PATIENTS DURING AND AFTER ENCEPHALOPATHY
significant indirect of encephalopathy. was a
correlation between R and the stage
These initial results, therefore, support the hypothesis of a biochemical mechanism for hepatic and respiratory encephalopathy which present analogous clinical pictures.
common
Service de Réanimation Médicale, Laboratoire Central de Biochimie, and INSERM U 56, Centre Hospitalier de Bicêtre, 94270 Le Kremlin Bicêtre, France
J. L. RICOME M. FENEANT F. LEMONNIER PH. AUZEPY
5. Hughes IE, Radman S. Relative toxicity of amitriptyline, imipramine, maprotiline and miansenn after intravenous infusion in conscious rabbits. Br J Clin Pharmacol 1978; 5: Suppl 19-20. 1. Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soetters PB. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery 1976; 80: 77-91.
don older and established compounds for newer drugs whose toxic potential has not yet been fully revealed. Animal experiments are unhelpful. Rabbits perfused intravenously with amitriptyline, imipramine, maprotiline, or mianserin5 developed convulsions at different dosages, and, although mianserin was the least toxic in this respect, the doses used were much higher than those used clinically, so the applicability of the experiment to man is questionable. We have, therefore, to rely on epidemiological data. The accuracy and usefulness of reports can be increased if those reporting data on seizures provide more detail, including information on preexisting disorders predisposing to epilepsy, the concomitant use of other potentially epileptogenic drugs, and withdrawal from drugs and or alcohol. I thank the Committee
on
Safety
Royal South Hants Hospital, Southampton, SO9 4PE *Drugs introduced in Britain for depression. t% of prescriptions. Source: Medical Data Index 1979, vol III (Intercontinental Medical Statistics, Harrow, Middlesex). Shares marked.. total less than 1.4% between them. C.S.M. as convulsions deaths shown in parentheses).
treported
to
or
grand-mal
convulsions
(numbers of
of Medicines for
supplying
data.
J. GUY EDWARDS
PLASMA AMINOACID IMBALANCE IN PORTAL-SYSTEMIC ENCEPHALOPATHY
SIR,-Dr James and colleagues (Oct. 13, p. 772) propose a hypothesis for portocaval encephalopathy in which there is a close biochemical relation between portal systemic encephaloepileptogenic potential of antidepressants, but should be interpathy (PSE) and the encephalopathy seen in chronic respirapreted with caution. Only about 10% of adverse reactions are tory failure. Having ourselves noted such a similarity of neuroreported to the C.S.M.,l although this figure could be higher logical symptoms in these disorders, we have been trying to for alarming reactions such as seizures; the percentage of cases find out if they have metabolic abnormalities in common, in reported may also vary with the drug, and clinicians often do respect of plasma aminoacids. not report well-known side-effects of a particular drug. The Patients with chronic respiratory failure were studied durnumber of reactions reported has to be seen in relation not ing a period of acute decompensation accompanied by an enceonly to the quantity of drug prescribed but also to the amount phalopathy. None had signs of hepatic insufficiency. Plasma taken by the patient, and compliance is seldom known accuaminoacids were determined by ion exchange chromatography is difficult to prove for drugs and unrately. Cause-and-effect (T.S.M.1) for fifteen patients before and after the disappearance of neurological signs. We calculated the ratio (R), defined wanted effects.2 as (Val+Leu+Ileu) — (Phe+Tyr), the variations of which I am doing a placebo-controlled study of mianserin and Fischer et al.’ have studied in chronic and acute hepatic encemaprotiline in depressive illness, and was therefore concerned phalopathy (normal range 3-3-5). We found R to be abnorabout reports of epileptic attacks in patients receiving maprotimally low in patients with encephalopathy. R rose significantly line,3.4 and, now, mianserin. I have been collecting background and in parallel with the decrease in P aC02 after the signs of data on patients whose seizures have allegedly been caused by encephalopathy had disappeared (table). Furthermore, there mianserin: in many of them the cause of the seizures seems very uncertain. One mentally subnormal patient who was reported as having had grand-mal attacks while taking mianserin had malignant hypertension and hypertensive retinopathy. His consultant did not think that mianserin was the cause of the attacks, because of the severe hypertension and because the patient had been taking mianserin for 10 months before they occurred. In another case the patient was suspected of having an organic brain disease which itself could have caused the attack. A third patient, an alcoholic, was withdrawing from large dosages of diazepam when the seizure happened. In other instances patients were concurrently receiving other potentially epileptogenic drugs or were being withdrawn from benzodiazepines.
Despite the difficulties in interpretation,
some of the figures The number of seizures reported in patients on amitriptyline and imipramine is small, even though these drugs have been marketed for a long time and have a large share of the market. In contrast, many cases have been associated with maprotiline, a drug that has been marketed in Britain for only a few years. Perhaps we should not readily aban-
call for
comment.
D. The use and abuse of psychotrophic drugs. Scott Med J 1971; 16: 345-49. 2. Edwards JG. Unwanted effects of psychotropic drugs; I. Some general considerations. Practitioner 1977 218: 556-62. 3. Shepherd GAA, Kerr F. Maprotiline hydrochloride and grand-mal seizures. Br Med Jl 1978; 1: 1523. 4. Hall MJ, Russell RI. Maprotiline hydrochloride and grand-mal seizures. Br Med J 1978; ii: 961. 1.
Dunlop
ARTERIAL BLOOD GAS ANALYSES AND R VALUES IN FIFTEEN PATIENTS DURING AND AFTER ENCEPHALOPATHY
significant indirect of encephalopathy. was a
correlation between R and the stage
These initial results, therefore, support the hypothesis of a biochemical mechanism for hepatic and respiratory encephalopathy which present analogous clinical pictures.
common
Service de Réanimation Médicale, Laboratoire Central de Biochimie, and INSERM U 56, Centre Hospitalier de Bicêtre, 94270 Le Kremlin Bicêtre, France
J. L. RICOME M. FENEANT F. LEMONNIER PH. AUZEPY
5. Hughes IE, Radman S. Relative toxicity of amitriptyline, imipramine, maprotiline and miansenn after intravenous infusion in conscious rabbits. Br J Clin Pharmacol 1978; 5: Suppl 19-20. 1. Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soetters PB. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery 1976; 80: 77-91.
