1368

lacking in concentration with sleep/wakefulness disturbances during treatment with PPA (’Monydrin’; Draco). After nine days she had vivid paranoid misconceptions and episodic muscular twitchings in the legs. The symptoms disappeared within 24 h after cessation of the drug. A 17-year-old was admitted mental hospital three times within a few months with signs and symptoms of acute mania-like psychosis with excessive motor excitement, aggressive behaviour, and elevated mood with uncontrollable thought and speech. During the third admission he deteriorated with hallucinosis and confusion. After recovery it was revealed that he had taken large quantities of PPA (rinexin) and PPA and brompheniramine (’Rinomar’; Leo) before each episode. The therapeutic and prophylactic effects of PPA in upper respiratory tract infections and in serous otitis media have been questioned. 1-6 Since psychic disturbances, including psychotic episodes, seem to be a problem, the prescribing of drugs containing PPA should be more restricted. to a

Paediatrics Clinic I,

Östra Sjukhuset, S-416 85

Gothenburg, Sweden

GUNNAR NORVENIUS

Department of Drugs, National Board of Health and Welfare,

ERIK WIDERLÖV

Box 607, S-751 25 Uppsala

GUDMAR LÖNNERHOLM

VILOXAZINE AND MIGRAINE

SIR,-During an open study of the bicyclic tetrahydroxazine antidepressant viloxazine hydrochloride (’Vivalan’) we found a high frequency of severe headache. Thirty depressed patients started treatment with viloxazine at 150 mg/day in divided doses, increasing by 50 mg/day every week to 300 mg/ day if well tolerated. We asked about side-effects each week. Fourteen patients continued on the drug for the 6-week trial period, and nine of them complained of headaches. Among the sixteen drop-outs, ten withdrew because of adverse effects, of whom six had severe headaches. Three patients described classical migraine symptoms. Case .—An 18-year-old woman was referred after an epsiode of She had a 3-month history of social withdrawal, tearfulness, and poor attention, following a broken romance. After 5 days of treatment with viloxazine she had several severe left supraorbital headaches accompanied by nausea and visual disturbances "like flashes". The headaches were followed by a feeling of "slowness". Viloxazine was continued without recurrence of these symptoms. Case 2.-A 54-year-old man presented with social withdrawal, tearfulness, diurnal variation of mood, and suicidal ideation. A previous episode of depression had responded to antidepressants. During the third week of treatment with viloxazine he had a severe right-sided headache associated with "difficulty in seeing things properly". With continued medication there was no recurrence. Case 3.-A 31-year-old woman presented in the outpatient clinic with a history of tearfulness, diurnal variations of mood, suicidal ideas, and sleep and appetite disturbances. She complained of severe headache throughout the trial. During the sixth week of viloxazine treatment she awoke early on several occasions with a severe one-sided headache accompanied by nausea.

self-poisoning.

None of these three patients had a personal or family history of migraine. Three other patients had severe one-sided headaches which did not recur after spontaneous omission of their medication. One of them had a history of migraine, and she claimed that while taking viloxazine her right-sided headaches

with blurring of vision were accompanied by new symptoms of mild photophobia, weakness, and nausea. Her headache remitted after one day without tablets. Thus in a group of thirty patients on viloxazine 50% had headaches, in several cases accompanied by nausea. The three patients described in detail and two others with severe onesided headaches had a migraine-like syndrome in the absence of any history of migraine, suggesting a causal relationship to the viloxazine treatment. Nausea and vomiting have been reported with viloxazine,’ though the nausea is generally ascribed to a local gastrointestinal action; its association with headache suggests cerebrovascular or central mechanism. The biological basis of migraine remains unresolved, but there is general agreement on the involvement of cranial and extracranial blood vessels. An initial vasoconstriction, probably due to a local release of noradrenaline acting on a-adrenoreceptors, seems to be associated with the prodromal phase of the syndrome, while a secondary vasodilatation (or reactive hyperxmia) is a feature of the headache phase of an attack. Factors known to precipitate migraine include drugs which potentiate or mimic the effects of the monoamines noradrenaline and 5-hydroxytryptamine (5-HT). Viloxazine inhibits noradrenaline reuptake in both central and peripheral nervous tissue24 and potentiates certain effects of 5-HT, probably by a presynaptic releasing action,3,5 These properties might, in susceptible individuals, induce cerebrovascular vasoconstriction and lead to side-effects characteristic of migraine. Other centrally acting drugs with pharmacological properties similar to those of viloxazine can also cause headache-e.g., tricyclic antidepressants’ (most of which block noradrenaline reuptake) and fenfluramineapotent 5-HT releasing agent. Although in our trial with viloxazine the side-effects tended to emerge after several days of treatment, the headache problem was transitory and subsided with continued medication. Academic Unit for Clinical

Psychopharmacology, Guy’s Hospital Medical School, London SE1

T. R. E. BARNES* T. KIDGER

Research (Biology) Department, I.C.I. Pharmaceuticals Division,

Alderley Park, Macclesfield, Cheshire

D. T. GREENWOOD

*Present address: Department of Psychiatry, University of School, New Addenbrookes Hospital, Cambridge CB2 2QQ.

Cambridge

Clinical

ANTIDEPRESSANTS AND CONVULSIONS

SIR,-Reports by Dr Tyrer and his colleagues (Oct. 13, p. 798) and by Dr Mikhail (Nov. 3, p. 969) of seizures in patients taking mianserin call for a fresh look at the incidence of seizures and related problems in patients taking antidepressants. The number of cases of convulsions reported to the Committee on Safety of Medicines (C.S.M.) up to November, 1979, is shown in the table, which also gives the percentage share of the 8 812 000 prescriptions for antidepressants issued between April, 1978, and June, 1979. The figures give some idea of the 1. Pinder RM, Brogden RN, Speight TM, Avery GS. Viloxazine A review of its pharmacological properties and therapeutic efficacy in depressive ill-

Drugs 1977; 13: 401-21, pharmacology of viloxazine (vivalan). J Int Med Res 1975; 3 suppl 3: 18-28.

ness.

2. Greenwood DT. Animal

3.

Kjellman N-I M, Harder H, Lindwall L. Synnerstad B. Long-term treatment with brompheniramine and phenylpropanolamine in recurrent otitis media: a double-blind study. Otolaryngol 1978; 7: 257-61. 4. Meistrup-Larsen KI, Mygind N, Thomsen J, Sørensen H, Vesterhauge S. Oral norephedrine in the treatment of acute otitis media. Results of a double-blind, placebo-controlled trial. Acta Otolaryngol 1978; 86: 248-50. 5. Olson AL, Klein SW, Charney E, JB, McInerny TK, Miller RL, Nazarian LF, Cunningham D. Prevention and therapy of serous otitis media by oral decongestant: A double-blind study in pediatric practice. Pediatrics 1978; 61: 679-84. 6. Randall JE, Hendley JO. A decongestant-antihistamine mixture in the prevention of otitis media in children with colds. Pediatrics 1979; 63: 483-85.

3.

Lippmann W, Pugsley TA. Effects of viloxazine, an antidepressant agent, on biogenic uptake mechanisms and related activities. Can J Physiol Pharmacol 1976; 54: 494-509. 4. Blackburn TP, Foster GA, Greenwood DT, Howe R. Effects of viloxazine, its optical isomers and its ma)or metabolites on biogenic amine uptake mechanisms in vitro and in vivo. Eur J Pharmaol 1978; 52: 367-74. 5. Martin IL, Baker GB, Mitchell PR. The effects of viloxazine on the transport of noradrenaline, dopamine, 5-hydroxytryptamine and gamma-aminobutyric acid in rat brain tissue. Neuropharmacology 1978; 17: 421-23. 6. Wheatley D. Psychopharmacology in family practice. London: Heinemann, 1973. 7. Sicuteri F, Del Berne E, Anselmi B. Fenfluramine headache. Headache

1976; 16: 185-88.

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.