307 PHENOXYBENZAMINE IN ANOREXIA NERVOSA

SIR,-Several symptoms of anorexia

nervosa suggest that of mechamsms" activity biological "satiety might be contributing to this disorder. In an 1873 description of the anorexia patient, Lasegue stated:’ "At first, she feels uneasiness about food, vague sensations of fullness, suffering, and gastralgin postprandium, or rather coming from the commencement of the repast... The patient thinks to herself that " the best remedy for this ... will be to diminish her food..." Later studies substantiate Lasegue’s description. There is a normal sense of hunger2and even preoccupation with food4 but attempts to eat result immediately in a sense of fullness;34 frequently a patient’s appetite will "break through"3 with episodes of bulimia followed quickly by induced vomiting.3 " Although satiety has been previously related to the function of the ventromedial nucleus of the hypothalamus (V.M.N.in animals,’ data on rodents now suggest that the biochemical mechanism of satiety is related to catecholamine mnervation entering or passing through the v.M.N. from other areas.6 Specific lesions of the nucleus locus cceruleus in stump-tail monkeys produce extreme hyperphagia associated with decreased noradrenaline concentrations in locus coeruleus projection areas while dopamine concentrations are normal. Other studies in which dopamine was also depleted led to hypophagia in monkeys.8 These data support a reciprocal effect of dopamine and noradrenaline, with decreases ’in dopamine leading to decreased appetite and decreases in noradrenaline leading to diminished satiation.9 A "dopamine theory" explaining the appetite changes in anorexia nervosa has previously been expoundedlo and some preliminary studies of the effects of increasing dopamine by levodopa have been reported." Unfortunately, such treatment might also increase noradrenaline with a resulting increase in satiety. We propose that excessive noradrenaline activity may be associated with and contributory to the ingestive components of some human appetite disorders, and that this effect may be diminished clinically by the use of the a-adrenergic blocking agent phenoxybenzamine. This hypothesis is supported by a trial of a and an blocking agent in a 21-year-old White, single woman with symptoms of primary anorexia nervosa. The patient was admitted for evaluation of psychiatric symptoms, weighing 56 kg, was refusing food and losing weight. In the present or a previous episode she had lost greater than 25% of body-weight, had amenorrhoea, obsession with a fat body image, food-hoarding and occasional bulimia followed by forced vomiting. In addition she had a family constellation and pre-morbid history consistent with classic descriptions of primary anorexia nervosa.4 During the 17-day evaluation period she was on no medication and lost weight at a rate of about 150 g/day. After a brief period of forced feeding with some weight gain, she was allowed to eat ad libitum while she was treated "single blind" with the jj-adrenergic blocking agent propranolol in doses from 40 to 480 mg/day for 13 days without serious side-effects. This treatment produced no significant change in the rate of weight loss (see figure) compared with the slope of the 17-day baseline period. After 7 days off drugs she was started on the a-adrenergic blocker, phenoxybenzamine at 10 mg/day. She appeared to gain weight until postural hypotension and nausea at 30 mg/day required discontinuation of the drug for 2 days during which weight loss resumed. She was restarted on 20 mg/day for an 11-day

increased

E. C. (in translation) in Evolution of Psychosomatic Concepts (edited by M. R. Kaufman and M. Hirman); p. 145. New York, 1964 2. Garfinkel, P. A. Psychol Med. 1974, 4, 309 3 Thoma, H. Anorexia Nervosa New York, 1967. 4 Bruch, H. J nerv. ment. Dis. 1970, 150, 51. 5 Miller, N E., Bailey, C. J., Stevenson,J A. F. Science, 1950, 112, 256 6. Kapatos, G., Gold, R. M Pharmac Biochem Behav. 1973, 1, 81 7. Redmond, D E , and others Unpublished. 8. Redmond, D E., Jr, Hinrichs, R H., Maas, J. W., Kling, A. Science, 1973, 181, 1256 9 Margules, D L J comp. Physiol. Psychol. 1970, 73, 1. 10. Mawson, A R, Psychol Med 1974, 4, 289 11 Johoson, A J, Knorr, N G Lancet, 1974, ii, 591. 1.

Lasègue,

-

.

during which there were no side-effects and she gained weight at a rate of 270 g/day (see figure). This brief clinical trial and the animal data suggesting specific and opposite effects of dopamine and noradrenalme on the control of ingestive behaviours support further testing of x-adrenergic blockers in patients with anorexia nervosa and other possibly related human appetite disorders.

trial

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D. E. REDMOND, A. SWANN G. R. HENINGER

Psychiatric Research Unit, Yale University, New

Haven, Connecticut 06510, U.S.A.

JR.

WHEN DO GALLSTONES MATTER?

SiR,—You suggest that there is

no

association between

gallstones and fatty dyspepsia or symptoms such as belching and bloating. Your advice is to be more careful in selecting patients with "symptomatic gallstones" for cholecystectomy. Your opinion is opposed by the worldwide agreement that symptomatic gallstones have to be removed.2-4 Furthermore, most surgeons and internists now agree that asymptomatic gallstones also have to be removed or at least treated conserva-

tively.’-’ prospective studies of untreated patients with asymptogallstones, 50% were found to pass to symptomatic disease; 20% of them developed severe complications with high mortality rate. 1-7 10 There was no significant difference, as far as the outcome is concerned, between the symptom-free patient who became symptomatic and the patient who was symptomatic from the beginning. This suggests that, at least in a proportion of the cases, the asymptomatic state is a step in the natural history of the disease, and it is only a matter of time before symptoms In

matic

appear.

Cholecystectomy is the treatment of choice. In Malm04 the mortality from cholecystectomy in the years 1954-63 was only 0-22%, and in ages under 60 it was only 0- 13%. I do not disagree with you that in many cases there is no association of symptoms with the presence of gallstones or that cholecystectomy sometimes does not cure the patient of fatty 1 2. 3. 4 5. 6 7 8. 9. 10

Lancet, 1976, i, 1061. W J. Am med. Ass. 1941, 56, 1021 Lund, J. Ann Surg. 1960, 151, 153. Wenckert, A., Robertson, B. Gastroenterology, 1966, 50, 376. Comfort, M. W., Gray, H. K., Wilson, J. M. Ann. Surg. 1948, 128, 931. Colcock, B P., Killen, L. H , Leach, J. Am. J. Surg. 1967, 113, 44. Method, L M., Harrison, W H., Frable, W J Archs Surg. 1962, 85, 338. Peskin, K. Surg. Clins N. Am 1973, 53, 1063. Schoenfield, L J. Gastroenterology, 1974, 67, 725. Moore, L Sth. med J 1951, 44, 1027.

Mayo,

,

Letter: Phenoxybenzamine in anorexia nervosa.

307 PHENOXYBENZAMINE IN ANOREXIA NERVOSA SIR,-Several symptoms of anorexia nervosa suggest that of mechamsms" activity biological "satiety might be...
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